CRYSTALLIZED CYTOPLASMIC TIE2 RECEPTOR TYROSINE KINASE DOMAIN AND METHOD OF DETERMINING AND DESIGNING MODULATORS OF THE SAME

Abstract: A solved three-dimensional crystal structure of a cytoplasmic Tie2 receptor tyrosine kinase domain is disclosed, along with four crystal forms of the cytoplasmic Tie2 receptor tyrosine kinase domain. The crystal forms include non- and monophosphorylated forms of the cytoplasmic Tie2 receptor tyrosine kinase domain. Methods of designing modulators of the biological activity of the cytoplasmic Tie2 receptor tyrosine kinase domain are also disclosed.

Description: Description CRYSTALLIZED CYTOPLASMIC TIE2 RECEPTOR TYROSINE KINASE DOMAIN AND METHOD OF DETERMINING AND DESIGNING MODULATORS OF THE SAME Technical Field The present invention relates generally to the structure of the cytoplasmic Tie2 receptor tyrosine kinase domain, and particularly to the structure of the catalytic core, the kinase insert domain and the C-terminal tail of the cytoplasmic Tie2 receptor kinase domain. The invention further relates to methods by which modulators of the cytoplasmic Tie2 receptor kinase domain can be identified. Abbreviations ADP adenosine diphosphate A-loop activation loop AL activation loop Ang1 angiopoietin 1 Ang2 angiopoietin 2 Ang3 angiopoietin 3 Ang4 angiopoietin 4 APC allophyocyanin ATP adenosine triphosphate BSA bovine serum albumin cAPK cAMP dependent protein kinase CL catalytic loop CTT C-terminal tail DTT dithiothreitol EGF epidermal growth factor FGF fibroblast growth factor FGFR1 fibroblast growth factor receptor 1 HEPES N-2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid HPLC high performance liquid chromatography ig immunoglobulin IMAC immobilized metal affinity chromatography IR insulin receptor IRK insulin receptor kinase KID kinase insert domain kDa kilodalton(s) LCMS liquid chromatography mass spectrometry MS mass spectrometry NBL nucleotide binding loop NDP nucleotide diphosphate NTP nucleotide triphόsphate PAGE polyacrylamide gel electrophoresis PCR polymerase chain reaction PDGF platelet derived growth factor pi isoelectric point PTB phosphotyrosine binding PTK protein tyrosine kinase RMS root mean square RMSD root mean square deviation RTK receptor tyrosine kinase SDS sodium dodecyl sulfate Sf9 Spodoptera frugiperda 9 SH2 src homology 2 VEGFR1 vascular endothelial growth factor receptor 1 VEGFR2 vascular endothelial growth factor receptor 2 Background Art Growth factors play important roles in the control of cell growth, differentiation, metabolism and oncogenesis, notably through the cellular process of angiogenesis and vasculogenesis. The signals generated by a growth factor are transduced across the cellular membrane by transmembrane receptors specific for the growth factor. The diverse biological effects of growth factors are mediated by a large family of cell surface transmembrane receptors with intrinsic protein tyrosine kinase (PTK) activity. The extracellular portion of receptor PTKs contain the binding site for its particular growth factor/ligand, whereas the tyrosine kinase activity resides in the cytoplasmic portion. Binding of a growth factor to the extracellular domain of this receptor results in autophosphorylation of specific tyrosine residues in the cytoplasmic domain. These phosphotyrosines either stimulate PTK activity or serve as binding sites for downstream signaling proteins containing Src-homology 2 (SH2) or phosphotyrosine binding (PTB) domains. Eighteen classes or subfamilies of human receptor PTKs have been identified to date, including the insulin receptor (IR), EGF-receptor, PDGF receptor and FGF-receptor. Ligand-induced dimerization of receptors such as the EGF, PDGF and FGF receptors is thought to be essential for activation. Growth factors such as PDGF are dimeric molecules which, by themselves, are able to induce PDGF-receptor dimerization. However, FGFs are monomeric and are unable by themselves to induce receptor dimerization. Dimerization of FGF receptors is thought to be mediated by FGF in concert with heparin sulfate proteoglycans (soluble or cell surface bound). The identified receptor PTKs have been implicated in a variety of disease states, notably angiogenesis- and vasculogenesis-related conditions. Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel. It is recognized that angiogenesis plays a major role in the metastasis of a cancer. If this angiogenic activity could be repressed or eliminated, then the tumor, although present, would not grow. In the disease state, prevention of angiogenesis could avert the damage caused by the invasion of the new microvascular system. As noted, vasculogenesis and angiogenesis are critical processes in embryonic development as well as in a number of diseases states, including ischemic coronary artery disease, cancer, diabetic retinopathy and rheumatoid arthritis (Folkman & Shing, (1992) J. Biol. Chem. 267: 10931- 10934; Risau, (1995) FASAB J. 9: 926-933; Pepper, (1996) Vase. Med A: 259-266; Kuiper et al. (1998) Pharmacol. Res. 37: 1-16; Kumar & Fidler (1998) In Vivo 18: 27-34; Szekanecz, et al. (1998) J. Investig. Med. 46: 27- 41 ; Tolentino & Adamis, (1988) Int. Ophthalmol. Clin. 38: 77-94). Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. The diverse pathological disease states in which unregulated angiogenesis is present have been grouped together as angiogenic-dependent or angiogenic-associated diseases. While the precise molecular mechanisms that regulate these processes have not been fully elucidated, normal vascular development is known to be dependent on the function of several endothelial specific receptor tyrosine kinases (RTKs) (reviewed in Tallαuist et al., (1999) Oncogene 18: 7917-7932; Merenmies et al., (1997) Cell Growth Differ. 8: 3-10). These include the TIE RTKs, Tie1 and Tie2. Tie2 was cloned in 1993 (Ziegler et al.. (1993) Oncogene 8: 663-670) and is also known to those of skill in the art as "Tek." The vascular endothelial growth factor receptor kinases (VEGFRs) 1-4 are also believed to play an early role in vascular development processes, directing the differentiation of mesodermal cells into endothelial cells and the proliferation and migration of endothelial cells to form primitive tubular vessels (Ferrara & Davis-Smyth. (1997) Endocrine Rev. 18: 4-25; Borαstrδm et al.. (1996) Cancer Res. 56: 4032-4039; Adamis et al.. (1996) Arch. Ophthalmol. 114: 66-71.). The Tie RTKs are involved in the later stages of modulating cell-cell and cell-matrix interactions required for vascular remodeling and maturation (Koblizek et al.. (1998) Curr. Biol. 8: 529-532; Witzenbichler et al.. (1998) J. Biol. Chem. 273: 18514-18521). Receptor tyrosine kinases comprise an extracellular ligand-binding domain (Tie2 has extracellular Ig and EGF homology domains) and an intracellular kinase domain. Binding of extracellular ligand is believed to promote dimerization, leading to autophosphorylation and activation of the kinase domain (reviewed in Lemmon & Schlessinger. (1994) Trends Biochem. Sci. 19: 459-463.) Stringent regulation of the phosphorylation state and activity of the cytoplasmic Tie2 receptor tyrosine kinase domain (hereinafter "Tie2K") is crucial to normal vasculature development and maintenance. Tie2 activity is precisely regulated by the opposing actions of agonistic and antagonistic extracellular ligands (Davis et al.. (1996) Cell 87: 1161-1169; Maisonpierre et al.. (1997) Science 277: 55-60; Valenzuela et al.. (1999) Proc. Natl. Acad. Sci. USA 96: 1904-1909). Tie2 activation requires autophosphorylation in response to binding its agonists, Ang1 and Ang4, whereas inactivation occurs in response to Ang2 and Ang3. Tie2 mutations, which result in ligand-independent and enhanced autophosphorylation, cause hereditary venous malformations (Vikkula et al.. (1996) Cell 87: 1181-1190; Calvert et al.. (1999) Hum. Mol. Genet. 8: 1279-1289). Conversely, transgenic mice that express a kinase-inactive form of Tie2 or Tie2 null mice die in utero due to defects in their microvasculature (Sato et al.. (1995) Nature (London) 376: 70-74; Dumont et al.. (1994) Genes Dev. 8: 1897-1909.). Inactivation of Ang1 or overexpression of Ang2 produces similar defects (Maisonpierre et al.. (1997) Science 277: 55-60; Suri et al.. (1996) Cell 87, 1171-1180; Suri et al.. (1998) Science 282: 468-471). The broad clinical potential of antiangiogenic therapy is just now being realized. Inhibition of either vascular endothelial growth factor receptor 2 (VEGFR2) or Tie2 by small molecules, by antibodies generated against the extracellular domain or by gene therapy have all been shown to reduce tumor progression (Borostrόm et al.. (1996) Cancer Res. 56: 4032-4039; Lin et al.. (1998) Proc. Natl. Acad. Sci. USA 95: 8829-8834). Development in the area of therapeutic treatments for angiogenic and vasculogenic disorders in humans has been impeded, however, by the lack of a detailed structural understanding of Tie2. Detailed structural knowledge of the three- dimensional structure of the kinase domain (Tie2K) of this receptor will enhance the design of potent and selective modulators as therapeutic agents. Moreover, an in-depth understanding of the structure of Tie2K can be applied to homologous kinases and will enhance the understanding of the entire field of receptor tyrosine kinase research. Polypeptides, including Tie2K, have a three-dimensional structure determined by the primary amino acid sequence and the environment surrounding the polypeptide. This three-dimensional structure establishes the polypeptide's activity, stability, binding affinity, binding specificity, and other biochemical attributes. Thus, as noted above, knowledge of a protein's three- dimensional structure can provide much guidance in designing agents that mimic, inhibit, or improve its biological activity in soluble or membrane bound forms. The three-dimensional structure of a polypeptide can be determined in a number of ways. Many of the most precise methods employ X-ray crystallography (See, e.g., Van Holde. (1971) Physical Biochemistry. Prentice- Hall, N. J., 221-239). This technique relies on the ability of crystalline lattices to diffract X-rays or other forms of radiation. Diffraction experiments suitable for determining the three-dimensional structure of macromolecules typically require high-quality crystals. Unfortunately, such crystals have been unavailable for Tie2K as well as many other proteins of interest. Thus, high- quality diffracting crystals of Tie2K would assist the determination of its three- dimensional structure. Various methods for preparing crystalline proteins and polypeptides are known in the art (See, e.g., McPherson. et al.. (1989) Preparation and Analysis of Protein Crystals. Robert E. Krieger Publishing Company, Malabar, Florida; Weber. (1991) Advances in Protein Chemistry 41:1-36; U.S. Pat. No. 4,672,108; and U.S. Pat. No. 4,833,233). There are multiple approaches to crystallizing polypeptides and slight differences in protein sequence often require variations in crystallization conditions, especially when the crystals must be suitable for X-ray diffraction studies. Thus, in spite of significant research, many proteins remain uncrystallized. In addition to providing structural information, crystalline polypeptides provide other advantages. For example, the crystallization process itself further purifies the polypeptide, and satisfies one of the classical criteria for homogeneity. In fact, crystallization frequently provides unparalleled purification quality, removing impurities that are not removed by other purification methods such as HPLC, dialysis, conventional column chromatography, etc. Moreover, crystalline polypeptides are often stable at ambient temperatures and free of protease contamination and other degradation associated with solution storage. Crystalline polypeptides can also be useful as pharmaceutical preparations. Finally, crystallization techniques in general are largely free of problems such as denaturation associated with other stabilization methods (e.g., lyophilization). Once crystallization has been accomplished, crystallographic data provides useful structural information that can assist the design of compounds that can serve as agonists or antagonists, as described herein below. In addition, the crystal structure provides information useful to map the receptor binding domain which could then be mimicked by a small non-peptide molecule which can serve as an antagonist or agonist. In an effort to elucidate the mechanisms underlying kinase activation as well as direct efforts to producing drugs to alleviate disease states in humans, the crystal structure of such proteins is often sought to be determined. The crystal structures of several protein serine/threonine kinases have been reported: cyclic-AMP-dependent protein kinase (cAPK; Kniohton et aL, (1991) Science 253: 407-414); cyclin-dependent kinase 2 (CDK2; DeBondt et al.. (1993) Nature 363: 595-602); mitogen-activated protein kinase (MAPK; Zhang et al.. (1994) Nature 367: 704-711); and twitchin kinase (Hu_et aL, (1994) Nature 369: 581-584). However, the crystalline structures of only three receptor tyrosine kinases have been determined to date-- the unphosphorylated apo form of the tyrosine kinase domain of the insulin receptor (Hubbard et al.. (1994) Nature 372:746-754) and the phosphorylated tyrosine kinase domain of the insulin receptor complexed with substrate and an ATP analog (Hubbard, (1997) EMBO J. 16: 5572-5581); the unphosphorylated tyrosine kinase domain of FGFR1 in apo form and complexed with inhibitor (Mohammadi et al.. (1996) Cell 86: 577-587); and the phosphorylated apo form of VEGFR2 (McTigue et al.. (1999) Structure 7: 319- 330). Despite these reports, the ability to obtain crystalline forms of the tyrosine kinase domains of non-insulin receptor tyrosine kinases; i.e., cytoplasmic tyrosine kinases and/or receptor tyrosine kinases that undergo ligand-mediated dimerization, has not been realized. A particularly illuminating example is the EGF receptor; researchers armed with the knowledge of how to obtain crystals of the tyrosine kinase domains of both the insulin receptor and serine/threonine kinases have attempted to obtain crystals of the tyrosine kinase domain of EGF receptor without success. And until disclosure of the present invention presented herein below, a detailed three-dimensional crystal structure of Tie2K has not been solved. Clearly, the solved crystal structure of Tie2K would be invaluable in the design of modulators of Tie2K-mediated activity. Evaluation of the data obtained from the recent genome sequencing efforts has made it clear that Tie2 shares significant sequence homology with several hundred other kinases. Further, Tie2 shares the same three-dimensional fold with these other kinases. Thus, in theory, it might be considered feasible to design modulators of Tie2 based exclusively on the sequence and three-dimensional fold of a different kinase. This method, however, would likely be unproductive and certainly hindered by a lack of subtle structural details of the various binding sites and pertinent residues of Tie2K that a solved crystal structure would provide. The solved Tie2K crystal structure would be of immeasurable value in Tie2 modulator design because the solved crystal structure would provide structural details and insights necessary to design a modulator of Tie2 that maximizes preferred requirements for any modulator, potency and specificity. By exploiting the structural details obtained from a Tie2 crystal structure, it would be possible to design a Tie2 modulator that, despite Tie2's similarity with numerous other kinases, exploits the unique structural features of Tie2. A Tie2 modulator developed using structure-assisted design would take advantage of heretofore unknown Tie2 structural considerations and thus be much more effective than a modulator developed using homology-based design. Potential or existent homology models cannot provide the necessary degree of specificity. What is needed, therefore, is a crystallized form of the cytoplasmic Tie2 receptor kinase domain, Tie2K. Acquisition of Tie2K crystals will permit the three-dimensional structure of the cytoplasmic Tie2 receptor kinase domain to be determined. Knowledge of the three-dimensional structure of this polypeptide will facilitate the design of modulators of Tie2 receptor kinase activity. Such modulators can lead to therapeutic compounds to treat a wide range of vasculogenesis and angiogenesis-related disease states. Disclosure of the Invention A composition comprising a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide in monoclinic crystalline form is disclosed. Preferably, the crystalline form has a space group of P2t More preferably, the crystalline form has lattice constants of a = 66 A, b = 92 A, c = 70 A, = 90°, β = 108°, γ = 90°. Even more preferably, the crystalline form has a resolution of 2.2 A or better. A composition comprising a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide in orthorhombic crystalline form is also disclosed. Preferably, the crystalline form has a space group of P2i2-i2i. More preferably, the crystalline form has lattice constants of a = 79 A, b = 92 A, c = 109 A, α = 90°, β = 90°, γ = 90°. Even more preferably, the crystalline form has a resolution of 2.5 A or better. A composition comprising a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide in orthorhombic crystalline form is also disclosed. Preferably, the crystalline form has a space group of P2ι2ι2ι. More preferably, the crystalline form has lattice constants of a = 52 A, b = 77 A, c = 79 A, α = 90°, β = 90°, γ = 90°. Even more preferably, the crystalline form has a resolution of 2.2 A or better. A composition comprising a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide in orthorhombic crystalline form and having a space group of C222- I and lattice constants of a = 95 A, b = 114 A, c = 78 A, α = 90°, β = 90°, γ = 90° is also disclosed. Preferably, the crystalline form has a resolution of 2.1 A or better. A method for determining the three-dimensional structure of a crystallized substantially pure cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide to a resolution of 2.2 A or better is disclosed. The method comprises: (a) crystallizing the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; and (b) analyzing the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide to determine the three-dimensional structure of the crystallized Tie2 receptor tyrosine kinase domain polypeptide. A method of designing a modulator of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide is also disclosed. The method comprises: (a) designing a potential modulator of the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide that will form bonds with amino acids in a substrate binding site based upon the structure the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; (b) synthesizing the modulator; and (c) determining whether the potential modulator modulates the activity of the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide. A method of designing a modulator of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide is also disclosed. The method comprises: (a) obtaining monoclinic or orthorhombic crystals of a substantially pure cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; (b) evaluating the three-dimensional structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; and (c) synthesizing potential modulators based on the three-dimensional crystal structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide. A method of screening for a modulator of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide is also disclosed. The method comprises: (a) providing a library of test samples; (b) contacting a crystalline form of cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide with each test sample; (c) detecting an interaction between a test sample and the crystalline form of cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; (d) identifying a test sample that interacts with a substantially pure cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; and (e) isolating a test sample that interacts with a substantially pure cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide. Also disclosed is an isolated and substantially pure nucleic acid sequence, the nucleic acid sequence coding for a Y897/Y1048F/S1119A Tie2K mutant polypeptide. A substantially pure Y897/Y1048F/S1119A Tie2K mutant polypeptide is also disclosed. Accordingly, it is an object of the present invention to provide a novel crystalline form of a Tie2K polypeptide. The object is achieved in whole or in part by the present invention. An object of the invention having been stated hereinabove, other objects will be evident as the description proceeds, when taken in connection with the accompanying Laboratory Examples and Figures as best described hereinbelow. Brief Description of the Drawings Figure 1 is a computer-generated ribbon diagram depicting the overall fold of Tie2K. The β-strands are labeled β1, β2, β3, β4, β5, β7 and β8. Alpha helices are labeled αC, αD, αE, αF, αG, αH and αl. The nucleotide binding loop is designated NBL, the activation loop is labeled AL, the kinase insert domain is labeled KID and the C-terminal tail is labeled CTT. The amino and carboxy-termini are denoted by N and C. Breaks in the chain occur between β-strand β3 and α-helix αC and in the activation loop due to crystal disorder. The figure was prepared with the RIBBONS software program (Carson & Bugg. (1986) J. Mol. Graphics 4: 121-122). An additional helix found in some kinases and located between helices αE and αF is labeled αEF, in accordance with the convention adopted by researchers in the field. Figure 2A is a computer-generated ribbon diagram depicting the N- terminal domains of Tie2K and FGFR1 in which the α-carbons of the β-sheets have been superimposed. The N-termini of each structure are labeled as N F for FGFR1 and N τ for Tie2K. The C-termini overlap and are labeled as CC. Beta strands β1, β2, β3, β4 and β5 are labeled. Nucleotide binding loop NBL is labeled. Helix αC is also labeled. The dashed line indicates the position of the disordered loop connecting β-strand β3 and α-helix αC in Tie2K. Figure 2B is a computer-generated ribbon diagram depicting the C- terminal domains of Tie2K and FGFR1 in which the α-carbons of the α-helices have been superimposed. The C-terminal tail of Tie2K is labeled CTT and the kinase insert domain for Tie2K is labeled KID. The C-terminal tail of FGFR1 is labeled C F and the C-terminal tail of Tie2K is labeled C τ . The N termini are labeled NN. Alpha helices αD, αE, αF, αG, αH and αl are labeled. Figures 2A and 2B were prepared with the QUANTA™ software program (QUANTA™, Release 4.0. California, San Diego, 1994). An additional helix found in some kinases and located between helices αE and αF is labeled αEF, in accordance with the convention adopted by researchers in the field. Figure 3A is a computer-generated image depicting the activation, nucleotide binding and catalytic loops of Tie2K. The nucleotide binding loop is labeled NBL, and α-helix αC is shown. The activation loop is designated AL. The lysine and glutamic acid residues that form a salt bridge, K855 and E872, are shown. The aspartate and arginine of the catalytic HDRLAAR motif (SEQ ID NO: 12), D964 and R963, are labeled in the figure. The aspartate and phenylalanine of the AspPheGly motif at the start of the activation loop, F983 and D982, are also labeled. Loops disordered in the crystal structures are indicated by dashed lines. Figure 3B is a computer-generated image depicting the activation, nucleotide binding and catalytic loops of activated IRK. The nucleotide binding loop is labeled NBL, and α-helix αC is also shown. The activation loop is designated AL. Residues of IRK that correspond to the residues of Tie2K labeled in Figure 3A are shown in Figure 3B. Specifically, the lysine and glutamic acid residues that form a salt bridge, K1030 and E1047 are labeled. The aspartate and arginine of the catalytic HDRLAAR motif (SEQ ID NO: 12), D1132 and R1131, are identified in the figure. The aspartate and phenylalanine of the AspPheGly motif at the start of the activation loop, F1151 and D1150, are also labeled. Figure 3C is a computer-generated image depicting the activation, nucleotide binding and catalytic loops of unphosphorylated FGFR1. The nucleotide binding loop is labeled NBL, and α-helix αC is also shown. The activation loop is designated AL. Residues of FGFR1 that correspond to the residues of Tie2K labeled in Figure 3A are shown in Figure 3C. Specifically, the lysine and glutamic acid residues that form a salt bridge, K514 and E531 are labeled. The aspartate and arginine of the catalytic HDRLAAR motif (SEQ ID NO: 12), D623 and R622, are labeled in the figure. The aspartate and phenylalanine of the AspPheGly motif at the start of the activation loop, F642 and D641, are also labeled. Figures 3A-3C were generated with the QUANTA™ software program. Figure 4 is a computer-generated image of the Tie2K ATP binding site. The superposition of the N-terminal β-sheets of Tie2K and activated IRK is shown. C α 's of β1- β5 were used to superimpose the structures of Tie2K and activated IRK (Hubbard et al.. PDB ID: 1IR3; Accession No. P06213; available online at http://www.rcsb.org/pdb/ ). The nucleotide binding site of Tie2K is labeled as NBL, and ATP is shown in a bound conformation. Figure 4 was prepared with the QUANTA™ software program. Figure 5 is a computer-generated image depicting the kinase insert domain and C-terminal tail of Tie2K. A ribbon diagram of the KIDs of Tie2K and IRK in which the α-carbons of the C-terminal domain α-helices have been superimposed is shown, α-helices αD, αE, αF and αH are labeled in the figure. The KID and C-terminal tail for Tie2K are labeled as KID T and CTT, respectively. The KID for IRK is labeled KID|. Tyrosine 1101 (Y1101) and tyrosine 1112 (Y1112) of Tie2K are labeled. Figure 5 was prepared with the QUANTA™ software program. Figure 6 is a computer-generated image depicting a noncrystallographic Tie2K dimer. The backbones of the two Tie2K polypeptides in the asymmetric unit are shown. The activation loops for the two Tie2K polypeptides are labeled AL. The nucleotide binding loops for the two Tie2K polypeptides are labeled NBL. The active site is labeled AS. A crystal contact is conserved at the noncrystallographic two-fold axis, and primarily involves the β1 structural elements. The noncrystallographic two¬ fold axis and the dimer interface are indicated by an extended horizontal arrow. The crystal contact occurs at the interface of the two Tie2K structures and is centered around the labeled β1 structures. Figure 6 was prepared with the QUANTA™ software program. Detailed Description of the Invention L Definitions Following long-standing patent law convention, the terms "a" and "an" mean "one or more" when used in this application, including the claims. As used herein, the term "Tie2K" means the kinase domain of the Tie2 protein. In the context of mutant generation and analysis, the term is intended to include mutants having a mutation in the Tie2K domain, which is a component of the entire Tie2 protein. Thus, in the context of mutants, the term "Tie2K" is intended to include Tie2 proteins with a mutation in the Tie2K domain. As used herein, the term "angiogenesis" means the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals undergo angiogenesis only in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. As used herein, the term "endothelium" means a thin layer of flat epithelial cells that lines serous cavities, lymph vessels, and blood vessels. As used herein, the term "endothelial modulating activity" means the capability of a molecule to modulate angiogenesis in general and, for example, to stimulate or inhibit the growth of endothelial cells in culture. As used herein, the term "mutation" carries its traditional connotation and means a change, inherited, naturally occurring or introduced, in a nucleic acid or polypeptide sequence, and is used in its sense as generally known to those of skill in the art. As used herein, the term "labeled" means the attachment of a moiety, capable of detection by spectroscopic, radiologic or other methods, to a probe molecule. As used herein, the term "target cell" refers to a cell, into which it is desired to insert a nucleic acid sequence or polypeptide, or to otherwise effect a modification from conditions known to be standard in the unmodified cell. A nucleic acid sequence introduced into a target cell can be of variable length. Additionally, a nucleic acid sequence can enter a target cell as a component of a plasmid or other vector or as a naked sequence. As used herein, the term "transcription" means a cellular process involving the interaction of an RNA polymerase with a gene that directs the expression as RNA of the structural information present in the coding sequences of the gene. The process includes, but is not limited to, the following steps: (a) the transcription initiation, (b) transcript elongation, (c) transcript splicing, (d) transcript capping, (e) transcript termination, (f) transcript polyadenylation, (g) nuclear export of the transcript, (h) transcript editing, and (i) stabilizing the transcript. As used herein, the term "expression" generally refers to the cellular processes by which a biologically active polypeptide is produced from RNA. As used herein, the term "transcription factor" means a cytoplasmic or nuclear protein which binds to such gene, or binds to an RNA transcript of such gene, or binds to another protein which binds to such gene or such RNA transcript or another protein which in turn binds to such gene or such RNA transcript, so as to thereby modulate expression of the gene. Such modulation can additionally be achieved by other mechanisms; the essence of "transcription factor for a gene" is that the level of transcription of the gene is altered in some way. As used herein, the term "hybridization" means the binding of a probe molecule, a molecule to which a detectable moiety has been bound, to a target sample. As used herein, the term "detecting" means confirming the presence of a target entity by observing the occurrence of a detectable signal, such as a radiologic or spectroscopic signal that will appear exclusively in the presence of the target entity. As used herein, the term "sequencing" means determining the ordered linear sequence of nucleic acids or amino acids of a DNA or protein target sample, using conventional manual or automated laboratory techniques. As used herein, the term "isolated" means oligonucleotides substantially free of other nucleic acids, proteins, lipids, carbohydrates or other materials with which they can be associated, such association being either in cellular material or in a synthesis medium. The term can also be applied to polypeptides, in which case the polypeptide will be substantially free of nucleic acids, carbohydrates, lipids and other undesired polypeptides. As used herein, the term "substantially pure" means that the polynucleotide or polypeptide is substantially free of the sequences and molecules with which it is associated in its natural state, and those molecules used in the isolation procedure. The term "substantially free" means that the sample is at least 50%, preferably at least 70%, more preferably 80% and most preferably 90% free of the materials and compounds with which is it associated in nature. As used herein, the term "primer" means a sequence comprising two or more deoxyribonucleotides or ribonucleotides, preferably more than three, and more preferably more than eight and most preferably at least about 20 nucleotides of an exonic or intronic region. Such oligonucleotides are preferably between ten and thirty bases in length. As used herein, the term "DNA segment" means a DNA molecule that has been isolated free of total genomic DNA of a particular species. For example, a DNA segment encoding a Tie2 or Tie2K polypeptide refers to a DNA segment that contains SEQ ID NO: 1 , SEQ ID NO: 3 or SEQ ID NO: 5, yet is isolated away from, or purified free from, total genomic DNA of a source species, such as Homo sapiens. Included within the term "DNA segment" are DNA segments and smaller fragments of such segments, and also recombinant vectors, including, for example, plasmids, cosmids, phages, viruses, and the like. As used herein, the phrase "enhancer-promoter" means a composite unit that contains both enhancer and promoter elements. An enhancer- promoter is operatively linked to a coding sequence that encodes at least one gene product. As used herein, the phrase "operatively linked" means that an enhancer-promoter is connected to a coding sequence in such a way that the transcription of that coding sequence is controlled and regulated by that enhancer-promoter. Techniques for operatively linking an enhancer-promoter to a coding sequence are well known in the art; the precise orientation and location relative to a coding sequence of interest is dependent, inter alia, upon the specific nature of the enhancer-promoter. As used herein, the term "candidate substance" means a substance that is believed to interact with another moiety, for example a given ligand that is believed to interact with a complete Tie2 or Tie2K polypeptide, or fragment thereof, and which can be subsequently evaluated for such an interaction. Representative candidate compounds or substrates include xenobiotics such as drugs and other therapeutic agents, carcinogens and environmental pollutants, natural products and extracts, as well as endobiotics such as steroids, fatty acids and prostaglandins. Other examples of candidate substances that can be investigated using the methods of the present invention include, but are not restricted to, agonists and antagonists of a Tie2 or Tie2K polypeptide, toxins and venoms, viral epitopes, hormones (e.g., opioid peptides, steroids, etc.), hormone receptors, peptides, enzymes, enzyme substrates, co-factors, lectins, sugars, oligonucleotides or nucleic acids, oligosaccharides, proteins, small molecules and monoclonal antibodies. As used herein, the term "biological activity" means any observable effect flowing from interaction between a Tie2 or Tie2K polypeptide and a ligand. Representative, but non-limiting, examples of biological activity in the context of the present invention include Tie2 autophosphorylation, dimerization of Tie2, angiogenesis, and vasculogenesis. As used herein, the term "modified" means an alteration from an entity's normally occurring state. An entity can be modified by removing discrete chemical units or by adding discrete chemical units. The term "modified" encompasses detectable labels as well as those entities added as aids in purification. As used herein, the terms "structure coordinates" and "structural coordinates" are interchangeable and mean mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of a Tie2K molecule in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal. Those of skill in the art understand that a set of structure coordinates determined by X-ray crystallography is not without standard error. For the purpose of this invention, any set of structure coordinates for Tie2K or a Tie2K mutant that have a root mean square (RMS) deviation from ideal of no more than 1 A, when superimposed using the polypeptide backbone atoms on the structure coordinates listed in Tables 2-5, shall be considered identical. As used herein, the term "asymmetric unit" means part of a symmetric object from which the whole is built up by repeats. Thus, it is the smallest unit from which the object can be generated by the symmetry operations of its point group. As used herein, the term "molecular replacement" means a method that involves generating a preliminary model of Tie2K or Tie2K mutant crystal whose structure coordinates are unknown, by orienting and positioning a molecule whose structure coordinates are known (e.g., FGFR1 coordinates from Tables 6-10) within the unit cell of the unknown crystal so as best to account for the observed diffraction pattern of the unknown crystal. Phases can then be calculated from this model and combined with the observed amplitudes to give an approximate Fourier synthesis of the structure whose coordinates are unknown. This, in turn, can be subject to any of the several forms of refinement to provide a final, accurate structure of the unknown crystal (Lattman. (1985) in Methods in Enzymology, 115: 55-77). Using the structure coordinates of Tie2K provided by this invention, molecular replacement can be used to determine the structure coordinates of a crystalline mutant or homologue of Tie2K or of a different crystal form of Tie2K. As used herein, the terms "β-sheet" and "beta sheet" are interchangeable and mean the conformation of a polypeptide chain stretched into an extended zig-zig conformation. Portions of polypeptide chains that run "parallel" all run in the same direction. Polypeptide chains that are "antiparallel" run in the opposite direction from the parallel chains. As used herein, the terms "α-helix" and "alpha helix" are interchangeable and mean the conformation of a polypeptide chain wherein the polypeptide backbone is wound around the long axis of the molecule in a left-handed or right-handed direction. The R groups of the amino acids protrude outward from the helical backbone, wherein the repeating unit of the structure is a single turn of the helix, which extends about 0.56 nm along the long axis. As used herein, the term "mutant" means a polypeptide which is obtained by replacing at least one amino acid residue in a native Tie2 or Tie2K polypeptide with a different amino acid residue and/or by adding and/or deleting amino acid residues within the native polypeptide or at the N- and/or C-terminus of a polypeptide corresponding to a native Tie2 or Tie2K and which has substantially the same three-dimensional structure as the native Tie2 or Tie2K from which it is derived. By having substantially the same three- dimensional structure is meant having a set of atomic structure coordinates that have a root mean square deviation (RMS deviation) of less than or equal to about 1A when superimposed with the atomic structure coordinates of the native Tie2 or Tie2K from which the mutant is derived when at least about 50% to 100% of the C α atoms of the native Tie2 or Tie2K are included in the superposition. A mutant can have, but need not have, autophosphorylation activity. As used herein, the term "space group" means a group or array of operations consistent with an infinitely extended regularly repeating pattern. It is the symmetry of a three-dimensional structure, or the arrangement of symmetry elements of a crystal. There are 230 space group symmetries possible; however, there are only 65 space group symmetries available for biological structures. As used herein, the term "symmetry" means some spatial manipulation of an object resulting in an indistinguishable object. A symmetric object can, therefore, be superimposed on itself by some operation. As used herein, the term "unit cell" means the fundamental portion of a crystal structure that is repeated infinitely by translation in three dimensions. A unit cell is characterized by three vectors a, b, and c, not located in one plane, which form the edges of a parallelepiped. Angles α, β and γ define the angles between the vectors: angle α is the angle between vectors b and c; angle β is the angle between vectors a and c; and angle γ is the angle between vectors a and b. The entire volume of a crystal can be constructed by regular assembly of unit cells; each unit cell comprises a complete representation of the unit of pattern, the repetition of which builds up the crystal. As used herein, "monoclinic unit cell" means a unit cell wherein a ≠b ≠ c and α = γ = 90° and β ≠ 90°. The vectors a, b and c describe the unit cell edges and the angles α, β, and γ describe the unit cell angles. As used herein, "orthorhombic unit cell" means a unit cell wherein a ≠b ≠ c; and α = β = γ = 90°. The vectors a, b and c describe the unit cell edges and the angles α, β, and γ describe the unit cell angles. As used herein, the term "crystal lattice" means the array of points defined by the vertices of packed unit cells. As used herein, the term "active site" means that site in the Tie2K domain where substrate peptide binding, ATP binding and catalysis occur. For Tie2, the active site comprises at least the activation loop and the nucleotide binding loop. As used herein, the term "activation loop" refers to a loop in tyrosine kinase domains between the conserved AspPheGly sequence (residues 982- 984 in Tie2K) and the conserved AlaProGlu sequence (residues 1006-1008 in Tie2K) that is believed to act as a regulatory loop. As used herein, the terms "nucleotide-binding loop" and "glycine-rich loop" are synonymous and mean a loop in an RTK which contains the protein kinase-conserved glycine-rich consensus sequence. In Tie2K, this region corresponds to residues 831-836. As used herein, the term "autophosphorylation site" means a residue or residues in Tie2K that is phosphorylated by a domain of Tie2 itself. As used herein, the term "juxtamembrane region" means that portion of Tie2K located between the transmembrane helix and the tyrosine kinase domain, specifically, the first 35 cytoplasmic residues of Tie2K. As used herein, the terms "kinase insert" and "kinase insert domain" are synonymous and mean an additional domain not found in non-receptor tyrosine kinases or serine/threonine kinases. It is found between helices αD and αE in the C-terminal domain of receptor tyrosine kinases and can vary greatly in sequence and length. In Tie2K, the kinase insert domain (KID) is positioned between helices αD and αE in the C-terminal domain (residues 916-936). As used herein, the term "C-terminal tail" means that region of an RTK that extends beyond the final helix of the C-terminal domain of the RTK. In Tie2K, the C-terminal region corresponds in sequence to amino acid residues 1099-1124. The C-terminal tail is known to interact with the SH2 domains of Grb2, Grb7, Grb14, Shp2 and other proteins. As used herein, the term "N-terminal domain" means that region of an RTK that has a defined structure and precedes in sequence the KID. In Tie2K the N-terminal domain corresponds in sequence to amino acid residues 808- 904 and comprises a twisted β-sheet and containing only a single α-helix. As used herein, the term "accessory proteins" means proteins that interact with Tie2 and modulate its activity. Interactions between Tie2 and its accessory proteins can be through hydrophobic interactions, hydrogen bonds, salt bridges or recognition of specific sequences or residues. For example, accessory proteins interact with Tie2 by binding specific phosphorylated tyrosine residues in the C-terminal tail of Tie2. As used herein, the term "modulate" means an increase, decrease, or other alteration of any or all chemical and biological activities or properties of a wild-type or mutant Tie2 or Tie2K polypeptide. \ Description of Tables Table 1 is a table summarizing the crystal and data statistics obtained from all four Tie2K crystal forms. Data on each of the unit cells is presented, including data on the crystal space group, unit cell dimensions, molecules per asymmetric cell and crystal resolution. Table 2 is a table the atomic structure coordinate data obtained from X- ray diffraction from Tie2K crystal form I. Table 3 is a table the atomic structure coordinate data obtained from X- ray diffraction from Tie2K crystal form II. Table 4 is a table the atomic structure coordinate data obtained from X- ray diffraction from Tie2K crystal form III. Table 5 is a table the atomic structure coordinate data obtained from X- ray diffraction from Tie2K crystal form IV. Tables 6-10 are tables of the atomic structure coordinate data obtained from X-ray diffraction from an FGFR1 crystal (Mohammadi et al.. PDB ID: 1FGK; Accession No. P11362; available online at http://www.rcsb.org/pdb/ ). The coordinate data from FGFR1 residues 464-485, 491-500, 506-578, 592- 647 and 651-761 were used in the molecular replacement solution of crystal forms l-IV. Table 6 is a table of the atomic coordinates for residues 464-485 (SEQ ID NO: 7) of FGFR1. Table 7 is a table of the atomic coordinates for residues 491-500 (SEQ ID NO: 8) of FGFR1. Table 8 is a table of the atomic coordinates for residues 506-578 (SEQ ID NO: 9) of FGFR1. Table 9 is a table of the atomic coordinates for residues 592-647 (SEQ ID O: 10) of FGFR1. Table 10 is a table of the atomic coordinates for residues 651-761 (SEQ ID NO: 11) of FGFR1. ML Formation. Characterization and Solution of Generated Tie2K Crystals III.A. Preparation of the Cytoplasmic Kinase Domain of A Tie2 Polypeptide Tie2K, comprising residues 808-1124 of Tie2, was expressed in baculovirus-infected Sf9 insect cells. The first 35 cytoplasmic residues, which are juxtaposed against the membrane, were not included in the construct. A hexahistidine tag was added at the N-terminus of the polypeptide to aid in the polypeptide purification process. Baculovirus-expressed Tie2K was heterogeneous with respect to phosphorylation. Preparations contained a mixture of proteins with zero to six phosphoryl groups that could not be fully separated by standard chromatographic procedures. III.B. Crystal Forms of the Cytoplasmic Kinase Domain of Tie2 Polypeptide Crystallization screens were initially performed using a mixture of the non-, mono- and diphosphorylated species. Three different crystal forms of Tie2K were obtained. As shown in Table 1 , crystal forms I and II contained unphosphorylated protein, while crystal form 111 contained mono- phosphorylated protein. A mutant form of Tie2K, discussed below, provided a fourth crystal form. III.C. Mapping of Phosphorylation Sites bv Mass Spectrometry Three (two major and one minor) phosphorylation sites were mapped by mass spectrometry. 111 -P. Mutation of Phosphorylation Sites The two major sites, tyrosine 897 and serine 1119, were mutated to phenylalanine and alanine respectively, while the minor site, tyrosine 1048, was mutated to phenylalanine. The mutant form of Tie2K was purified to homogeneity as unphosphorylated protein and gave rise to crystal form IV, coordinate data for which is presented in Table 5. III.E. Solving the Three-Dimensional Structure of Tie2K by Molecular Replacement The structure of crystal form I was solved by molecular replacement using the structure of the unphosphorylated kinase domain of FGFR1 (Mohammadi et al.. (1996) Cell 86: 577-87) as a search model. The structure was refined to an R-factor of 19% to a resolution of about 2.2 A. Six residues at the N-terminus, three residues at the C-terminus, four residues in the activation loop, and six residues connecting β3 and αC were disordered and could not be modeled. The structures of crystal forms II, 111 and IV were solved by molecular replacement using the structure determined for crystal form I. The Tie2K structure in all four crystal forms was essentially identical, suggesting that conformations observed in the structure are not due to crystal packing forces. Residues disordered in crystal form I were also disordered in crystal forms II, III and IV. Superposition of all backbone α-carbons yielded a root mean square deviation (RMSD) of 0.18 A for form I versus form II, 0.47 A for form I versus form III, and 0.45 A for form I versus form IV. III.F. The Three-Dimensional Structure of the Cytoplasmic Tie2 Receptor Kinase Domain The present invention discloses four crystalline forms of the Tie2K. Using these four crystalline forms, the three-dimensional structure of Tie2K was solved to a resolution of about 2.2 A. Crystal form I was solved using molecular replacement techniques. The solved structure of crystal form I was then used as a template for the solution of crystal forms II, III and IV using molecular replacement methodology. Crystal forms I and II comprise unphosphorylated protein. Crystal form III comprises monophosphorylated protein. Crystal form IV comprises unphosphorylated protein. A summary of the crystal data for all four crystal forms is presented in Table 1 , and coordinate data for crystal forms l-IV are presented in Tables 2-5, respectively. I11.F.1. Overview of the Three-Dimensional Structure of Tie2K A ribbon diagram of the C α backbone of Tie2K is depicted in Figure 1. The kinase secondary structural elements are labeled according to the convention adopted by researchers in the field and originally given for cAPK (Knighton et al.. (1991) Science 253: 407-413.). Tie2K folds into two domains, with catalysis occurring in a cleft between the two domains. As depicted in Figure 1 , residues in the N-terminal domain N are primarily responsible for ligating ATP, while residues in the C-terminal domain C are involved in catalysis and substrate binding. Continuing with Figure 1 , the N-terminal domain of Tie2K (residues 808-904) folds into a twisted β-sheet and one α-helix. The larger C-terminal domain (residues 905-1124) contains seven α-helices, helices αD through αl, and two anti-parallel β-strands, β7and β8. These two strands are positioned at the interdomain interface adjacent to the N-terminal β-sheet. Kinase insert domain KID comprises 2 short helical segments that pack against the C- terminal lobe and the extended C-terminal tail. Like other kinases, Tie2K also contains functionally important loop regions: the glycine-rich nucleotide binding loop NBL (residues 831-836), the catalytic loop CL (residues 962- 968) and the activation loop AL (residues 982-1008). III.F.2. Comparison of the Structure of Tie2K to the Structure of FGFR1 Of the reported kinase structures, the overall structure of Tie2K most closely resembles the catalytic domain of fibroblast growth factor receptor 1 (FGFR1, Mohammadi et al.. (1996) Cell 86: 577-87), with which it shares ~45% sequence identity. Superposition of the 5 β-strands in the N-terminal domains of Tie2K and FGFR1 yielded an N-terminal domain C α RMSD of 0.76 A; superposition of the C-terminal domains using α-carbons from the 7 α- helices gave a C-terminal domain C α RMSD of 0.58 A. Like unphosphorylated FGFR1 , Tie2K is in an opened conformation with a relative rotation of approximately 15° between the N- and C-terminal lobes when compared to the closed, active structure of insulin receptor kinase (IRK) (Hubbard. (1997) EMBO J. 16: 5572-5581 ), an RTK predicted to have similar structure. The beta sheet topologies in the N-terminal domain of FGFR1 and Tie2K are quite similar, as depicted in Figure 2A. Significant differences are observed, however, in three distinct regions: the nucleotide binding loop NBL, the loops connecting β3-αC and β4-β5, and the position of the C-helix. Compared with FGFR1 , β strands β3, β4 and β5 of Tie2K contain one additional residue. This difference produces a change in the conformation of the loop regions connecting these sheets. The extension of the β3-4-5 sheet displaces residues in the C-helix of Tie2K by 2.5 to 5.5 A from their equivalent positions in FGFR1. Additionally, six Tie2K residues in the loop connecting β3 with αC, residues alanine 861 (A861) through histidine 866 (H866), are disordered in all four crystal forms. Therefore, only 3.5 turns of the C-helix are observed for Tie2K, as opposed to 5 turns observed in FGFR1. In the N-terminal domain of a number of kinases, two conserved, charged residues form a salt bridge in order to correctly position the α and β phosphates of ATP for catalysis. In Tie2K these residues correspond to lysine 855 (K855) on β3 and glutamate 872 (E872) on helix αC. Due to the shift in helix αC, these residues are about 7.2 A apart compared with the approximately 3-4 A distance observed in other kinase structures (Hubbard et aL, (1994) Nature 372: 746-754; Hubbard, (1997) EMBO J. 16: 5572-5581 ; Mohammadi et al.. (1996) Ce// 86: 577-87; McTioue et al.. (1999) Structure 7: 319-330). While the shift in helix αC is not as dramatic as the shift observed in the structures of inactive cdk2 as compared to the activated cdk2/cyclinA complex, which known to be 8.5 A (Jeffrey et al.. (1995) Nature 376: 313- 320), the conformational change required to bring these residues into proper alignment for ATP binding is not obvious. Figure 2B demonstrates that the C-terminal lobes of Tie2K and FGFR1 are also quite similar in structure and position, except for the positions of the activation loop AL and kinase insert domain KID, which is disordered in FGFR1. The C-terminal tail was included in the Tie2K construct but not in FGFR1, IRK and VEGR2; and is observed in the Tie2K crystal structure. Continuing with Figure 2B, the C-terminal tail has an extended conformation that packs under the KID, runs along helices αl, αF and αE, and ends near the substrate binding site. lll.F.3.The Activation Loop and Catalytic Residues Protein kinases contain a large flexible loop, called the activation loop, or A-loop, whose conformation is believed to regulate kinase activity. In many kinases, the conformation of the A-loop is controlled by the phosphorylation of specific residues within the A-loop. Johnson et al.. (1996) Cell 85: 149-158. The activation loop generally begins with a conserved AspPheGly sequence, identified in Tie2K as residues 982-984, and ends at a conserved AlaProGlu, identified in Tie2K as residues 1006-1008. Johnson et al.. (1996) Cell 85: 149- 158. In structures of inactive kinases, this loop often blocks either the substrate or ATP binding sites. Hubbard et al.. (1994) Nature 372: 746-754; Mohammadi et al.. (1996) Ce// 86: 577-87; McTigue et al.. (1999) Structure 7: 319-330. Upon phosphorylation, the A-loop is repositioned to contact residues in the C-terminal domain. Hubbard (1997) EMBO J. 16: 5572-5581. The activating phosphate can then interact with a cluster of basic residues, which includes a conserved arginine (corresponding to arginine 963, R963, in Tie2K) that precedes a catalytic aspartate residue (aspartate 964, D964, in Tie2K). The aspartyl residue of the AspPheGly motif ligates a Mg 2+ ion, which in turn contacts the β and γ phosphates of ATP. The activation loop of Tie2K corresponds to residues 982-1008 and contains a single tyrosine at position 992. The conserved AlaProGlu sequence of protein kinases occurs as AlalleGlu in Tie2. In the Tie2K structure of the present invention, the A-loop more closely resembles that of activated IRK than that seen for inactive, unphosphorylated FGFR1, as is depicted in Figure 3A, 3B and 3C. Continuing with Figures 3A-3C, four residues near the N-terminal end of Tie2K's A-loop AL, residues threonine 996 (T996) through arginine 999 (R999), are disordered. All attempts to phosphorylate Y992 (which is found in A-loop AL) using purified wild-type protein have been unsuccessful. However, when tyrosines 897 and 1048 and serine 1119 were mutated to phenylalanine and alanine respectively, the purified protein could be quantitatively phosphorylated on Y992. While it is not the applicants' desire to be bound to any theory, it is postulated that these observations suggest that the mode by which Tie2 is activated is complex and could differ from that found in other RTKs (Johnson et al., (1996) Cell 85, 149-158). The conformation of the conserved AspPheGly motif of the Tie2K activation loop is also significantly different than that seen in other kinase structures (Hubbard et al.. (1994) Nature 372: 746-754; Hubbard (1997) EMBO J. 16: 5572-5581 ; Mohammadi et al.. (1996) Cell 86: 577-87; McTigue et al.. (1999) Structure 7: 319-330). The side chains of D982 and F983 point in directions opposite to those observed in nonphosphorylated FGFR1 and activated IRK (Figures 3A, 3B and 3C). As seen in Figures 3A-3C, the aspartate 982 (D982) side chain is directed towards the back of the pocket, away from the ATP binding site. The Tie2K side chain of phenylalanine 983 (F983) extends towards solvent and is sandwiched between the side chains of K855 of β3 and E872 of helix αC, the conserved residues which form the salt bridge required to correctly position the phosphates of ATP. Although the Tie2K activation loop adopts an "active-like" conformation overall, the AspPheGly motif at the beginning of this loop has a conformation which could potentially inhibit ATP binding. The catalytic loop of protein kinases lies between helices αE and β7 and contains an invariant aspartic acid (D964 in Tie2K) that serves as the catalytic base in the phosphotransfer reaction (Johnson et al.. (1996) Cell 85: 149-158). The catalytic loops of Tie2, FGFR1 , VEGFR2 and IRK are identical in sequence, each containing the HRDLAARN (SEQ ID NO: 12) sequence. Hubbard et al.. (1994) Nature 372: 746-754; Mohammadi et al.. (1996) Cell 86: 577-87; McTioue et al.. (1999) Structure 7: 319-330. As depicted in Figures 3A-3C, the backbone and side chain positions of this loop in Tie2K are similar to those in the unliganded FGFR1 and VEGFR2 and in the ternary phosphorylated IRK complex structures. lll.FAThe Nucleotide Binding Loop The nucleotide binding loop of an RTK contains residues responsible for binding the triphosphate moiety of ATP in the correct position for catalysis (Johnson et al.. (1996) Cell 85: 149-158). This glycine-rich loop is believed to be quite flexible and is often either disordered or has high b-factors (which are indicative of the degree of flexibility of a protein segment) in many unliganded kinase structures. Mohammadi et al.. (1996) Cell 86: 577-87; McTioue et al.. (1999) Structure 7: 319-330. In Tie2K, this loop adopts a unique self-inhibitory conformation with residues 832-836 occupying the ATP binding site, exemplified in Figure 4. The γ carboxylate of glutamine 832 (E832), if protonated, could form a hydrogen bond with the backbone carbonyl of glutamine 903 (E903). The backbone carbonyl of E903 presumably participates in the binding of ATP through a hydrogen bond to the 6-amino group of the nucleotide. The α and β phosphate binding sites of ATP are occupied by asparagine 834 (N834) and glycine 836 (G836). Phenylalanine 835 (F835) sits in a pocket at the back of the site formed by the side chains of lysine 855 (K855), isoleucine 886 (1886), isoleucine 902 (1902) and phenylalanine 983 (F983). Asparagine 834 (N834) occupies the site of the conserved aspartate of the AspPheGly motif in the A- loop that binds Mg 2+ and the γ phosphate of ATP. ATP was modeled into the active site of Tie2K based on the structure of activated IRK. As depicted in Figure 4, the nucleotide binding loop NBL precludes the binding of ATP. lll.F.δ.The Kinase Insert Domain Many RTKs contain a kinase insert domain (KID) of variable length and sequence between helices αD and αE in their C-terminal domain. This insert can be as short as 12 residues or as long as 97 residues, as in IRK and platelet derived growth factor receptor β (PDGFRβ), respectively. Hubbard et §L., (1994) Nature 372: 746-754; Heidaran (1991) Mol. Cell. Biol. 11: 134-142. Deletion or mutation of this insert in other kinases revealed that the KID is not necessary for intrinsic kinase activity. McTigue et al.. (1999) Structure 7: 319- 330; Heidaran et al.. (1991) Mol. Cell. Biol. 11: 134-142; Taylor et al.. (1989) EMBO J. 8: 2029-2037. However, this kinase insert domain might be important for protein-protein interactions involved in signal transduction via autophosphorylation of KID tyrosine residues. Heidaran et al.. (1991) Mol. Cell. Biol. 11: 134-142; Taylor et al.. (1989) EMBO J. 8: 2029-2037. In Tie2, this region corresponds to residues 916-936 and does not contain tyrosine residues. Due to the lack of sequence conservation in this domain, structural conservation is also not expected. In FGFR1, the KID is apparently quite mobile and disordered in the crystal structure of the unliganded protein. (Mohammadi et al.. Cell 86: 577-87) In VEGFR2, the KID was deleted in the construct used for structural studies (McTigue et al.. (1999) Structure 7: 319- 330). In the IRK structure, this region, comprising proline 1093 (P1093) to glycine 1110 (G1100), is proline-rich and forms a loop that folds towards the N-terminal domain (Hubbard et al.. (1994) Nature 372: 746-754). In Tie2K, the KID comprises two short helical segments connected by a turn, as depicted in Figure 5, and packs against residues 1104-1112 in the C-terminal tail. III.F.6. Interaction of the C-terminal Tail With Accessory Proteins The C-terminal tail of Tie2 has been shown to bind a number of proteins containing src homology 2 (SH2) and phosphotyrosine binding (PTB) domains in a phosphotyrosine-dependent manner. Numerous reports suggest that tyrosines 1101 (Y1101) and 1112 (Y1112) (as shown in Figure 5) in the C-terminal tail interact with the SH2 domains of Grb2, Grb7, Grb14, Shp2, the p85 subunit of PI3 kinase, and the PTB domain of Dok-R. Huang et a , (1995) Oncogene 11: 2097-2103; Jones & Dumont. (1998) Oncogene 17: 1097-1108; Kontos et al.. (1998) Mol. Cell. Biol. 18: 4131-4140; Jones et al.. (1999) J. Biol. Chem. 274: 30896-30905; Korpelainen et al.. (1999) Oncogene 18: 1 -8. In the unliganded crystal structure of the present invention, the hydroxyls of tyrosine 1101 (Y1101) and tyrosine 1112 (Y1112) are not solvent exposed, and appear to play a structural role, as depicted in Figure 5. The hydroxyl of Y1101 hydrogen bonds to the side chain of E759 (not shown in Figure 5) while the phenyl ring is packed between the side chains of M757 and K762 (not shown in Figure 5). The hydroxyl of Y1112 hydrogen bonds to the main chain NH and carbonyl oxygen of L579 and A592 respectively. The phenyl ring of Y1112 sits in a hydrophobic pocket formed by the side chains of L696, L579, F1114, and R577 (not shown in Figure 5). Mass spectroscopic analysis of the baculovirus-expressed Tie2K showed that Y897 and Y1048, which point directly out into solvent, are partially phosphorylated. But, there was no evidence for phosphorylation of Y1101 or Y1112. In the unphosphorylated FGFR1 and IRK structures, the activation loop blocks access to the substrate binding site. Hubbard et al.. (1994) Nature 372: 746-754; Mohammadi et al.. (1996) Cell 86: 577-87. Continuing with Figure 5, in Tie2K the activation loop adopts an "active-like" conformation while the end of the C-terminal tail CTT could block access to the substrate binding site. The last ordered residue E1120 (not shown in Figure 5) of the C-terminal tail, CTT, is positioned where the substrate residue preceding the tyrosine would bind. While it is not the applicants' desire to be bound to any theory, it is postulated that in view of this data, the C-terminal tail undergoes a conformational change upon activation of the protein, exposing both the substrate binding site and Y1101 and Y1112 for phosphorylation and signaling. III.G. Mutational Analysis of Tie2K Crystal Forms Two mutations in the N-terminal domain of Tie2, R849W and Y897S, have been identified in humans, and segregate with an autosomal dominant condition known as Vascular Dysmorphogenesis. Vikkula et al.. (1996) Cell 87: 1181-1190; Calvert et al.. (1999) Hum. Mol. Genet. 8: 1279-1289. This condition is characterized by lesions consisting of haphazardly-arranged, dilated blood vessels that lack or have a reduced smooth muscle layer and little to no supportive tissue. These two mutations result in ligand- independent hyperphosphorylation of Tie2. Vikkula et al.. (1996) Cell 87: 1181-1190; Calvert et al.. (1999) Hum. Mol. Genet. 8: 1279-1289. It has been suggested that they either relieve autoinhibition of the kinase or promote dimerization in the absence of ligand (Vikkula et al.. (1996) Cell 87: 1181- 1190). The Tie2K crystal forms I and II of the present invention, which comprise unphosphorylated protein, have 2 molecules in the asymmetric unit. Crystal form III, comprising protein mono-phosphorylated at the tyrosine 897 position, contains only one molecule in the asymmetric unit. In the two unphosphorylated crystal forms, one crystal contact (~1096 A 2 ) is conserved at the noncrystallographic two-fold axis, depicted in Figure 6 as an extended horizontal arrow. This contact primarily involves β1 as well as residues from the ends of β2, β3 and β4 in the N-terminal domain. Both residues R849 and Y897 (not shown in Figure 6) sit at this crystal contact. Phenylalanine 826, valine 829 and leucine 839 form the hydrophobic core of this interface. Tyrosine 897, tyrosine 899, arginine 849 and aspartic acid 828 are located at the edges of the interface. Arginine 849, the first residue of β3, makes a weak hydrogen bond to glutamine 837 of the neighboring molecule. The side chain of R849 is packed between the side chains of Y897 and V829 from the neighboring molecule. Tyrosine 897 is located on the loop connecting β4 and β5 and packs against arginine 849. While it is not the applicants' desire to be bound to any theory, it is postulated that mutation of arginine 849 to tryptophan could allow for better packing at this predominantly hydrophobic interface. Again, while it is not the applicants' desire to be bound to any theory, it is further postulated that phosphorylation of Y897 would be difficult to accommodate at this tight crystal contact and therefore would lead to crystal form III. If this extensive crystal contact is in fact a biologically significant dimer interface, the phosphorylation state of Y897 could be another mechanism of controlling the activity of Tie2. When Y897 is phosphorylated, the cytoplasmic kinase domains cannot dimerize; but when unphosphorylated or mutated to a serine, Tie2K dimerization would be favored. This is further supported by the observation that purified wild-type Tie2K, a significant fraction of which is phosphorylated on tyrosine 897, could not appreciably autophosphorylate tyrosine 992 in the activation loop. In contrast, the Y897F/Y1048F/S1119A mutant could autophosphorylate Y992, leading to an approximately 100-fold increase in kinase activity. Additionally, Tie2, when phosphorylated on Y897, has been shown to bind the protein tyrosine phosphatase Shp2, which can also play a role in down regulation of Tie2 activity. Huang et al.. (1995) Oncogene 11 : 2097-2103; Jones et al.. (1999) J. Biol. Chem. 274: 30896-30905. IV. Uses of Tie2K Crystals and the Three-Dimensional Structure of Tie2K IV.A. Design and Development of Tie2K Modulators The knowledge of the structure of the cytoplasmic Tie2 receptor tyrosine kinase domain, an aspect of the present invention, provides a tool for investigating the mechanism of action of the Tie2 and Tie2K polypeptides in a subject. For example, various computer models, as described herein, can predict binding of various substrate molecules to Tie2K. Upon discovering that such binding takes place, knowledge of the protein structure then allows design and synthesis of small molecules that mimic the functional binding of the substrate to Tie2K. This is the method of "rational" drug design, further described herein. Use of the isolated and purified Tie2K structure of the present invention in rational drug design is thus provided in accordance with the present invention. Rational drug design techniques are described in U.S. Patent Nos. 5,834,228 and 5,872,011 , incorporated herein in their entirety. IV.A.L Rational Drug Design A method of identifying modulators of the activity of Tie2 or Tie2K using rational drug design is provided in accordance with the present invention. The method comprises the steps of designing a potential modulator for the Tie2 or Tie2K polypeptide of the present invention that will form non-covalent bonds with amino acids at a binding site based upon a crystalline form of the Tie2 or Tie2K polypeptide; synthesizing the modulator; and determining whether the potential modulator modulates the activity of the Tie2 or Tie2K polypeptide. Modulators can be synthesized using techniques known to those of ordinary skill in the art. The determination of whether the modulator modulates the biological activity of the Tie2 or Tie2K polypeptide can be made in accordance with the screening methods disclosed herein, or by other screening methods known to those of skill in the art. Preferably, the Tie2 polypeptide comprises the amino acid sequence of SEQ ID NO: 2, and the Tie2K polypeptide comprises the amino acid sequence of SEQ ID NO: 4. In another preferred embodiment, the Tie2K polypeptide comprises the amino acid sequence of SEQ ID NO: 6. 1V.A.2. Methods for Using the Tie2K Structural Coordinates For Molecular Design For the first time, the present invention permits the use of molecular design techniques to design, select and synthesize chemical entities and compounds, including modulatory compounds, capable of binding to the active site or accessory binding site of Tie2 and Tie2K, in whole or in part. In accordance with the present invention the structure coordinates of crystalline Tie2K can be used to design compounds that bind to the Tie2K domain and alter the properties of Tie2K, e.g., autophosphorylation ability, in different ways. For example, the present invention provides for the design of compounds that act as competitive inhibitors of the Tie2 enzyme by binding to all, or a portion of, the binding sites on the Tie2K domain. The present invention also provides for the design of compounds that can act as uncompetitive inhibitors of the Tie2K enzyme. These compounds can bind to all, or a portion of, an accessory binding site of a Tie2 that is already binding its substrate and can, therefore, be more potent and less non-specific than known competitive inhibitors that compete only for the Tie2K substrate or nucleotide binding site. Similarly, non-competitive inhibitors that bind to and inhibit Tie2K, whether or not it is bound to another chemical entity, can be designed using the Tie2K structure coordinates of this invention. A second design approach is to probe a Tie2K crystal with molecules comprising a variety of different chemical entities to determine optimal sites for interaction between candidate Tie2K modulators and the polypeptide. For example, high resolution X-ray diffraction data collected from crystals saturated with solvent allows the determination of the site where each type of solvent molecule adheres. Small molecules that bind tightly to those sites can then be designed and synthesized and tested for their Tie2K modulator activity (Allen et al.. (1996) J. Phys. Chem. 100(7): 2606-2611). IV.A.3. Methods of Designing Tie2K Modulator Compounds The design of candidate substances, also referred to as "compounds" or "candidate compounds", that bind to or inhibit Tie2K according to the present invention generally involves consideration of two factors. First, the compound must be capable of physically and structurally associating with Tie2K. Non-covalent molecular interactions important in the association of Tie2K with its substrate include hydrogen bonding, van der Waals and hydrophobic interactions. Second, the compound must be able to assume a conformation that allows it to associate with Tie2K. Although certain portions of the compound will not directly participate in this association with Tie2K, those portions can still influence the overall conformation of the molecule. This, in turn, can have a significant impact on potency. Such conformational requirements include the overall three-dimensional structure and orientation of the chemical entity or compound in relation to all or a portion of the binding site, e.g., active site or accessory binding site of Tie2K, or the spacing between functional groups of a compound comprising several chemical entities that directly interact with Tie2K. The potential modulatory or binding effect of a chemical compound on Tie2K can be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques. If the theoretical structure of the given compound suggests insufficient interaction and association between it and Tie2K, synthesis and testing of the compound is obviated. However, if computer modeling indicates a strong interaction, the molecule can then be synthesized and tested for its ability to bind and inhibit Tie2K. In this manner, synthesis of unproductive or inoperative compounds can be avoided. A modulatory or other binding compound of Tie2K can be computationally evaluated and designed by means of a series of steps in which chemical entities or fragments are screened and selected for their ability to associate with the individual binding sites or other areas of Tie2K. One of ordinary skill in the art can use one of several methods to screen chemical entities or fragments for their ability to associate with Tie2K and, more particularly, with the individual binding sites of the Tie2K active site or an accessory binding site. This process can begin by visual inspection of, for example, the active site on a computer screen based on the Tie2K coordinates in Tables 2-5. Selected fragments or chemical entities can then be positioned in a variety of orientations, or docked, within an individual binding site of Tie2K as defined herein above. Docking can be accomplished using software programs such as those available under the tradenames QUANTA™ and SYBYL™ (Tripos, Inc., St. Louis, Missouri), followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as CHARM and AMBER. Specialized computer programs can also assist in the process of selecting fragments or chemical entities. These include: 1. GRID™ program, version 17 (Goodford. (1985) J. Med. Chem. 28: 849-857), which is available from Molecular Discovery Ltd., Oxford, UK; 2. MCSS™ program (Miranker & Karplus. (1991) Proteins 11: 29-34), which is available from Molecular Simulations, Inc., San Diego, California; 3. AUTODOCK™ 3.0 program (Goodsell & Olsen. (1990) Proteins 8: 195-202), which is available from the Scripps Research Institute, La Jolla, California; and 4. DOCK™ 4.0 program (Kuntz et al.. (1992) J. Mol. Biol. 161 : 269- 288), which is available from the University of California, San Francisco, California. Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or modulator. Assembly can be proceed by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of Tie2K. Manual model building using software such as QUANTA™ or SYBYL™ typically follows. Useful programs to aid one of ordinary skill in the art in connecting the individual chemical entities or fragments include: 1. CAVEAT™ program (Bartlett et al.. (1989) Special Pub., Royal Chem. Soc. 78: 182-196), which is available from the University of California, Berkeley, California; 2. 3D Database systems, such as MACCS-3D™ system program, which is available from MDL Information Systems, San Leandro, California. This area is reviewed in Martin. (1992) J. Med. Chem. 35: 2145-2154; and 3. HOOK™ program (Eisen et al.. (1994). Proteins: 19: 199-221), which is available from Molecular Simulations, Inc., San Diego, California. Instead of proceeding to build a Tie2K modulator in a step-wise fashion one fragment or chemical entity at a time as described above, modulatory or other Tie2K binding compounds can be designed as a whole or de novo using either an empty binding site or optionally including some portion(s) of a known modulator(s). Applicable methods can employ the following software programs: 1. LUDI™ program (Bohm. (1992) J. Comp. Aid. Molec. Design, 6: 61- 78), which is available from Molecular Simulations, Inc., San Diego, California; 2. LEGEND™ program (Nishibata & Itai, (1991) Tetrahedron 47: 8985); and 3. LEAPFROG™, which is available from Tripos Associates, St. Louis, Missouri. Other molecular modeling techniques can also be employed in accordance with this invention. See, e.g., Cohen et al.. (1990) J. Med. Chem. 33: 883-894. See also, Navia & Murcko, (1992) Current Opinions in Structural Biology 2: 202-210; U.S. Patent No. 6,008,033, herein incorporated by reference. Once a compound has been designed or selected by the above methods, the efficiency with which that compound can bind to Tie2K can be tested and optimized by computational evaluation. For example, a compound that has been designed or selected to function as a Tie2K modulator should also preferably traverse a volume not overlapping that occupied by the binding site when it is bound to its native ligand. An effective Tie2K modulator should preferably demonstrate a relatively small difference in energy between its bound and free states (i.e., a small deformation energy of binding). Thus, the most efficient Tie2K modulators should preferably be designed with a deformation energy of binding of not greater than about 10 kcal/mole, preferably, not greater than 7 kcal/mole. Tie2K modulators can interact with the enzyme in more than one conformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free compound and the average energy of the conformations observed when the modulator binds to the enzyme. A compound designed or selected as binding to Tie2K can be further computationally optimized so that in its bound state it would preferably lack repulsive electrostatic interaction with the target enzyme. Such non- complementary (e.g., electrostatic) interactions include repulsive charge- charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the modulator and the enzyme when the modulator is bound to Tie2K, preferably make a neutral or favorable contribution to the enthalpy of binding. Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interaction. Examples of programs designed for such uses include: 1. Gaussian 98, which is available from Gaussian, Inc., Pittsburgh, Pennsylvania; 2. AMBER™ program, version 6.0, which is available from the University of California at San Francisco; 3. QUANTA™ program, which is available from Molecular Simulations, Inc., San Diego, California; 4. CHARMm ® program, which is available from Molecular Simulations, Inc., San Diego, California; and 4. Insight II ® program, which is available from Molecular Simulations, Inc., San Diego, California. These programs can be implemented using a suitable computer system, for instance, a Silicon Graphics workstation, IRIS 4D/35 or IBM RISC/6000 workstation model 550. Other hardware systems and software packages will be apparent to those skilled in the art after review of the disclosure of the present invention presented herein. Once a Tie2K modulating compound has been optimally selected or designed, as described above, substitutions can then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally, initial substitutions are conservative, i.e., the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation should be avoided. Such substituted chemical compounds can then be analyzed for efficiency of fit to a Tie2K binding site using the same computer-based approaches described in detail above. IV.B. Method of Screening for Chemical and Biological Modulators of the Biological Activity of Tie2 Once a candidate modulator compound is designed and tested as described above, it can be further tested in a screening assay. A representative method of screening candidate substances for their ability to modulate the biological activity of Tie2K comprises: (a) providing a library of test samples; (b) contacting a crystalline form of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide with each test sample; (c) detecting an interaction between a test sample and the crystalline form of cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; (d) identifying a test sample that interacts with the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; and (e) isolating a test sample that interacts with the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide. A candidate substance identified according to the screening assay described herein has an ability to modulate the biological activity of the Tie2 and Tie2K polypeptides. Such a candidate compound has utility in the treatment of disorders and conditions associated with the biological activity of the Tie2 and Tie2K polypeptides, including vascular dysmorphogenesis. Candidate compounds can be hydrophilic, hydrophobic, polycyclic molecules, or any combination thereof, and are typically about 500-1 ,000 daltons in molecular weight. In a cell-free system, the method can comprise establishing a control system comprising a Tie2 or Tie2K polypeptide and a ligand which is capable of binding to the polypeptide; establishing a test system comprising a Tie2 or Tie2K polypeptides, the ligand, and a candidate compound; and determining whether the candidate compound modulates the activity of the polypeptide by comparison of the test and control systems. A representative ligand comprises a small molecule, and in this embodiment, the biological activity or property screened includes binding affinity. In another embodiment of the invention, the Tie2 or Tie2K polypeptide or a catalytic or immunogenic fragment or oligopeptide thereof, can be used for screening libraries of compounds in any of a variety of drug screening techniques. The libraries of compounds preferably comprise compounds designed and tested as described in section IV.A. above. The fragment employed in such screening can be free in solution, affixed to a solid support, borne on a cell surface, or located intracellulariy. The formation of binding complexes between the Tie2 or Tie2K polypeptide and the agent being tested can be measured. In a preferred embodiment, the Tie2 polypeptide has an amino acid sequence of SEQ ID NO: 2. When the Tie2K polypeptide is employed, a preferred embodiment comprises a Tie2K polypeptide having the amino acid sequence of SEQ ID NO: 4. A mutant Tie2K of the present invention, preferably having the amino acid sequence of SEQ ID NO: 6, can also be employed. Another technique for drug screening which can be used provides for high throughput screening of compounds having suitable binding affinity to the protein of interest as described in published PCT application WO 84/03564, herein incorporated by reference. In this method, as applied to a polypeptide of the present invention, large numbers of different small test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. The libraries of compounds preferably comprise compounds designed and tested as described in section IV.A. above. The test compounds are reacted with the polypeptide, or fragments thereof, and washed. Bound polypeptide is then detected by methods well known in the art. The purified polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques. Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support. In each of the foregoing embodiments, an interaction can be detected spectrophotometrically, radiologically or immunplogically. An interaction between a Tie2 or Tie2K polypeptide and a test sample can also be quantified. Such an interaction can be quantified by determining Tie2 or Tie2K activity. A screening assay of the present invention can also involve determining the ability of a candidate substance to modulate, i.e. inhibit or promote Tie2 or Tie2K biological activity and preferably, to thereby modulate the biological activity of Tie2 or Tie2K in target cells. Target cells can be either naturally occurring cells known to contain a polypeptide gene product of the present invention or transfected cells. The test samples can further comprise a cell or cell line that expresses the Tie2 or Tie2K polypeptide gene product of the present invention, for example, Xenopus oocytes expressing a foreign Tie2 or Tie2K. Such cell lines can be mammalian, or human, or they can from another organism, including but not limited to yeast. Representative assays include genetic screening assays and molecular biology screens such as a yeast two-hybrid screen that will effectively identify genes related to angiogenesis, vasculogenesis or a cellular process related to these biological phenomena. One version of the yeast two-hybrid system has been described (Chien et al.. (1991) Proc. Natl. Acad. Sci. USA, 88: 9578-82) and is commercially available from Clontech (Palo Alto, California). As is well known in the art, a screening assay can provide a cell under conditions suitable for testing the modulation of the biological activity of a Tie2 or Tie2K polypeptide. These conditions include but are not limited to pH, temperature, tonicity, the presence of relevant metabolic factors (e.g., metal ions such as for example Mg ++ , growth factors, or angiopoeitins), and relevant modifications to a Tie2 or Tie2K polypeptide such as phosphorylation. A Tie2 or Tie2K polypeptide of the present invention can be expressed and utilized in a prokaryotic or eukaryotic cell. The host cell can also be fractionated into sub-cellular fractions where a structure of interest can be found. For example, cells expressing the Tie2 or Tie2K polypeptide can be fractionated into the nuclei, the endoplasmic reticulum, vesicles, or the membrane surfaces of the cell. In accordance with the present invention there is also provided a rapid and high throughput screening method that relies on the methods described above. This screening method comprises separately contacting each of a plurality of substantially identical samples. In such a screening method the plurality of samples preferably comprises more than about 10 4 samples, or more preferably comprises more than about 5 x 10 4 samples. V. Design, Preparation and Structural Analysis of Additional Tie2 and Tie2K Mutants and Structural Eguivalents The present invention also provides for the generation of Tie2 and Tie2K mutants and the ability to solve the crystal structures of those that crystallize. More particularly, through the provision of the three-dimensional structure of Tie2K, desirableisites for mutation can be identified. The structure coordinates of Tie2K mutants provided in accordance with the present invention also facilitate the identification of related proteins or enzymes analogous to Tie2K in function, structure or both, (for example, FGFR), which can lead to novel therapeutic modes for treating or preventing a range of disease states. V.A. Sterically Similar Compounds A further aspect of the present invention is that other sterically similar compounds can be formulated to mimic the key portions of the Tie2K structure. Such compounds can be used in the same manner as the peptides of the present invention and hence are also functional equivalents. The generation of a structural functional equivalent can be achieved by the techniques of modeling and chemical design known to those of skill in the art and described herein. Modeling and chemicai design of Tie2K structural equivalents can be based on the structure coordinates of the present invention. It will be understood that all such sterically similar constructs fall within the scope of the present invention. Vj^ Tie2 Polypeptides The generation of chimeric Tie2 polypeptides is also an aspect of the present invention. Such a chimeric polypeptide can contain the Tie2K polypeptide or a portion of Tie2K, which can be fused to a candidate polypeptide or a suitable region of the candidate polypeptide, for example FGF. Throughout the instant disclosure it is intended that the term "mutant" encompass not only the polypeptide of Tie2K but chimeric proteins generated using Tie2K as well. It is intended that the following discussion of Tie2K mutants applies mutatis mutandis to chimeric Tie2 and Tie2K polypeptides and to structural equivalents thereof. In accordance with the present invention, a mutation can be directed to a particular site or combination of sites of wild-type Tie2K, i.e., an accessory binding site, the active site, or an autophosphorylation site can be chosen for mutagenesis. Similarly, a residue having a location on, at or near the surface of the polypeptide can be replaced, resulting in an altered surface charge of one or more charge units, as compared to the wild-type Tie2 and Tie2K. Alternatively, an amino acid residue in Tie2 or Tie2K can be chosen for replacement based on its hydrophilic or hydrophobic characteristics. Such mutants can be characterized by any one of several different properties as compared with wild-type Tie2K. For example, such mutants can have an altered surface charge of one or more charge units, or have an increase in overall stability. Or such mutants can have an altered substrate specificity in comparison with, or a higher specific activity than, wild-type Tie2 and Tie2K. The mutants of Tie2K prepared by this invention can be prepared in a number of ways. For example, the wild-type sequence of Tie2 or Tie2K can be mutated in those sites identified using this invention as desirable for mutation, by means of oligonucleotide-directed mutagenesis or other conventional methods, e.g. deletion. Alternatively, mutants of Tie2 or Tie2K can be generated by the site-specific replacement of a particular amino acid with an unnaturally occurring amino acid. In addition, Tie2 or Tie2K mutants can be generated through replacement of an amino acid residue, for example, a particular cysteine or methionine residue, with selenocysteine or selenomethionine. This can be achieved by growing a host organism capable of expressing either the wild-type or mutant polypeptide on a growth medium depleted of either natural cysteine or methionine (or both) but enriched in selenocysteine or selenomethionine (or both). Mutations can be introduced into a DNA sequence coding for Tie2K using synthetic oligonucleotides. These oligonucleotides contain nucleotide sequences flanking the desired mutation sites. Mutations can be generated in the full-length DNA sequence of Tie2K or in any sequence coding for polypeptide fragments of Tie2K. According to the present invention, a mutated Tie2K DNA sequence produced by the methods described above, or any alternative methods known in the art, can be expressed using an expression vector. An expression vector, as is well known in the art, typically includes elements that permit autonomous replication in a host cell independent of the host genome, and one or more phenotypic markers for selection purposes. Either prior to or after insertion of the DNA sequences surrounding the desired Tie2K mutant coding sequence, an expression vector also will include control sequences encoding a promoter, operator, ribosome binding site, translation initiation signal, and, optionally, a repressor gene or various activator genes and a signal for termination. In some embodiments, where secretion of the produced mutant is desired, nucleotides encoding a "signal sequence" can be inserted prior to the Tie2K mutant coding sequence. For expression under the direction of the control sequences, a desired DNA sequence must be operatively linked to the control sequences- i.e., they must have an appropriate start signal in front of the DNA sequence encoding the Tie2K mutant and maintaining the correct reading frame to permit expression of that sequence under the control of the control sequences and production of the desired product encoded by that Tie2K sequence. Any of a wide variety of well-known available expression vectors are useful to express the mutated Tie2K coding sequences of this invention. These include for example, vectors consisting of segments of chromosomal, non-chromosomal and synthetic DNA sequences, such as various known derivatives of SV40, known bacterial plasmids, e.g., plasmids from E. coli including col E1 , pCR1 , pBR322, pMB9 and their derivatives, wider host range plasmids, e.g., RP4, phage DNAs, e.g., the numerous derivatives of phage λ, e.g., NM 989, and other DNA phages, e.g., M13 and filamentous single stranded DNA phages, yeast plasmids and vectors derived from combinations of plasmids and phage DNAs, such as plasmids which have been modified to employ phage DNA or other expression control sequences. In the preferred embodiments of this invention, vectors amenable to expression in a baculovirus expression system are employed. In addition, any of a wide variety of expression control sequences- sequences that control the expression of a DNA sequence when operatively linked to it- can be used in these vectors to express the mutated DNA sequences according to this invention. Such useful expression control sequences, include, for example, the early and late promoters of SV40 for animal cells, the lac system, the trp system the TAC or TRC system, the major operator and promoter regions of phage λ, the control regions of fd coat protein, all for E. coli, the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase, e.g., Pho5, the promoters of the yeast α-mating factors for yeast, and other sequences known to control the expression of genes of prokaryotic or eukaryotic cells or their viruses, and various combinations thereof. A wide variety of hosts are also useful for producing mutated Tie2K polypeptides according to this invention. These hosts include, for example, bacteria, such as E. coli, Bacillus and Streptomyces, fungi, such as yeasts, and animal cells, such as CHO and COS-1 cells, plant cells, insect cells, such as Sf9 cells, and transgenic host cells. It should be understood that not all expression vectors and expression systems function in the same way to express mutated DNA sequences of this invention and to produce modified Tie2K or Tie2K mutants. Neither do all hosts function equally well with the same expression system. However, one of skill in the art can make a selection among these vectors, expression control sequences and hosts without undue experimentation and without departing from the scope of this invention. For example, an important consideration in selecting a vector will be the ability of the vector to replicate in a given host. The copy number of the vector, the ability to control that copy number, and the expression of any other proteins encoded by the vector, such as antibiotic markers, should also be considered. In selecting an expression control sequence, a variety of factors should also be considered. These include, for example, the relative strength of the system, its controllability, its compatibility with the DNA sequence encoding the modified Tie2K polypeptide of this invention, particularly with regard to potential secondary structures. Hosts should be selected by consideration of their compatibility with the chosen vector, the toxicity of the modified Tie2K to them, their ability to express mature products, their ability to fold proteins correctly, their fermentation requirements, the ease of the purification of the modified Tie2K from them and safety. Within these parameters, one of skill in the art can select various vector/expression control system/host combinations that will produce useful amounts of a mutant Tie2K. A mutant Tie2K produced in these systems can be purified by a variety of conventional steps and strategies, including those used to purify wild-type Tie2K. Once a Tie2K mutant(s) has been generated in the desired location, i.e., active site, accessory binding site or phosphorylation site, the mutants can be tested for any one of several properties of interest. For example, mutants can be screened for an altered charge at physiological pH. This is determined by measuring the mutant Tie2K isoelectric point (pi) in comparison with that of the wild-type parent. Isoelectric point can be measured by gel-electrophoresis according to the method of Wellner (Wellner, (1971) Analyt. Chem. 43: 597). A mutant with an altered surface charge is a Tie2K polypeptide containing a replacement amino acid located at the surface of the enzyme, as provided by the structural information of this invention, and an altered pi. V.C. Generation of an Engineered Tie2 or Tie2K Mutant In another aspect of the present invention, a unique Tie2 or Tie2K mutant can be generated. Such a mutant can facilitate purification and the study of Tie2's autophosphorylation abilities. Specifically, by mutating tyrosine 897 to phenylalanine, it is possible to obtain an activated Tie2 or Tie2K polypeptide. By mutating tyrosine 1048 to phenylalanine, it is possible to generate a mutant Tie2 or Tie2K polypeptide that allows for more homogeneous preparations of the polypeptide. Similarly, by mutating serine 1119 to alanine it is possible to generate a Tie2 or Tie2K mutant that allows for more homogeneous preparations of the polypeptide. These mutations can be present alone or in combination in a single Tie2 or Tie2K polypeptide, and can provide an activated mutant Tie2 or Tie2K polypeptide with enhanced purification properties. In a preferred embodiment, a mutant Tie2 or Tie2K of the present invention comprises the nucleic acid sequence shown in SEQ ID NO: 5. More preferably, a mutant Tie2 or Tie2K of the present invention comprises the amino acid sequence shown in SEQ ID NO: 6. Even more preferably, a mutant Tie2 or Tie2K of the present invention comprises three point mutations: tyrosine 897 is mutated to phenylalanine; tyrosine 1048 is mutated to phenylalanine and serine 1119 is mutated to alanine. As used in the following discussion, the term "engineered Tie2 or Tie2K mutant" refers to polypeptides having amino acid sequences which contain at least one of the mutations Y897F, Y1048F, or S1119A. The term also refers to Tie2 and Tie2K polypeptides which are capable of exerting a biological effect in that they comprise all or a part of the amino acid sequence of an engineered Tie2 or Tie2K mutant polypeptide of the present invention, or cross-react with antibodies raised against an engineered Tie2 or Tie2K mutant polypeptide, or retain all or some or an enhanced degree of the biological activity of the engineered Tie2 or Tie2K mutant amino acid sequence or protein. Such biological activity can include autophosphorylation or immunogenicity. The term "engineered Tie2 or Tie2K mutant" also includes analogs of an engineered Tie2 or Tie2K mutant polypeptide. By "analog" is intended that a DNA or polypeptide sequence can contain alterations relative to the sequences disclosed herein, yet retain all or some or an enhanced degree of the biological activity of those sequences. Analogs can be derived from genomic nucleotide sequences as are disclosed herein or from other organisms, or can be created synthetically. Those skilled in the art will appreciate that other analogs, as yet undisclosed or undiscovered, can be used to design and/or construct Tie2 or Tie2K mutant analogs. There is no need for an engineered Tie2 or Tie2K mutant polypeptide to comprise all or substantially all of the amino acid sequence of SEQ ID NO: 6. Shorter or longer sequences are anticipated to be of use in the invention; shorter sequences are herein referred to as "segments". Thus, the term "engineered Tie2 or Tie2K mutant" also includes fusion, chimeric or recombinant engineered Tie2 or Tie2K mutant polypeptides and proteins comprising sequences of the present invention. Methods of preparing such proteins are disclosed herein above and are known in the art. V.C.1 Seguence Similarity and Identity As used herein, the term "substantially similar" means that a particular sequence varies from nucleic acid sequence of SEQ ID NO: 5, or the amino acid sequence of SEQ ID NO: 6 by one or more deletions, substitutions, or additions, the net effect of which is to retain at least some of biological activity of the natural gene, gene product, or sequence. Such sequences include "mutant" or "polymorphic" sequences, or sequences in which the biological activity and/or the physical properties are altered to some degree but retains at least some or an enhanced degree of the original biological activity and/or physical properties. In determining nucleic acid sequences, all subject nucleic acid sequences capable of encoding substantially similar amino acid sequences are considered to be substantially similar to a reference nucleic acid sequence, regardless of differences in codon sequences or substitution of equivalent amino acids to create biologically functional equivalents. V.D. Seguences That are Substantially Identical to an Engineered Mutant Tie2K Seguence of the Present Invention Additionally, nucleic acids that are substantially identical to a nucleic acid sequence of an engineered Tie2 or Tie2K mutant of the present invention, e.g. allelic variants, genetically altered versions of the gene, etc., bind to an engineered Tie2 or Tie2K mutant sequence under stringent hybridization conditions. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes can be any species, e.g. primate species; rodents, such as rats and mice, canines, felines, bovines, equines, yeast, nematodes, etc. Between mammalian species, e.g. human and mouse, homologs have substantial sequence similarity, i.e. at least 75% sequence identity between nucleotide sequences. Sequence similarity is calculated based on a reference sequence, which can be a subset of a larger sequence, such as a conserved motif, coding region, flanking region, etc. A reference sequence will usually be at least about 18 nt long, more usually at least about 30 nt long, and can extend to the complete sequence that is being compared. Algorithms for sequence analysis are known in the art, such as BLAST, described in Altschul et al.. (1990) J. Mol. Biol. 215: 403-10. Percent identity or percent similarity of a DNA or peptide sequence can be determined, for example, by comparing sequence information using the GAP computer program, available from the University of Wisconsin Geneticist Computer Group. The GAP program utilizes the alignment method of Needleman et al.. (1970) J. Mol. Biol. 48: 443, as revised by Smith et al.. (1981) Adv. Appl. Math. 2:482. Briefly, the GAP program defines similarity as the number of aligned symbols (i.e., nucleotides or amino acids) which are similar, divided by the total number of symbols in the shorter of the two sequences. The preferred parameters for the GAP program are the default parameters, which do not impose a penalty for end gaps. See, e.g., Schwartz et al.. eds., (1979), Atlas of Protein Seguence and Structure, National Biomedical Research Foundation, pp. 357-358; Gribskov et al.. (1986) Nucl. Acids. Res. 14: 6745. The term "similarity" is contrasted with the term "identity". Similarity is defined as above; "identity", however, means a nucleic acid or amino acid sequence having the same amino acid at the same relative position in a given family member of a gene family. Homology and similarity are generally viewed as broader terms than the term identity. Biochemically similar amino acids, for example leucine/isoleucine or glutamate/aspartate, can be present at the same position- these are not identical per se, but are biochemically "similar." As disclosed herein, these are referred to as conservative differences or conservative substitutions. This differs from a conservative mutation at the DNA level, which changes the nucleotide sequence without making a change in the encoded amino acid, e.g. TCC to TCA, both of which encode serine. As used herein, DNA analog sequences are "substantially identical" to specific DNA sequences disclosed herein if: (a) the DNA analog sequence is derived from coding regions of the nucleic acid sequence shown in SEQ ID NO: 5; or (b) the DNA analog sequence is capable of hybridization of DNA sequences of (a) under stringent conditions and which encode a biologically active Tie2 or Tie2K gene product; or (c) the DNA sequences are degenerate as a result of alternative genetic code to the DNA analog sequences defined in (a) and/or (b). Substantially identical analog proteins and nucleic acids will have between about 70% and 80%, preferably between about 81% to about 90% or even more preferably between about 91 % and 99% sequence identity with the corresponding sequence of the native protein or nucleic acid. Sequences having lesser degrees of identity but comparable biological activity are considered to be equivalents. As used herein, "stringent conditions" means conditions of high stringency, for example 6XSSC, 0.2% polyvinylpyrrolidone, 0.2% Ficoll, 0.2% bovine serum albumin, 0.1% sodium dodecyl sulfate, 100 μg/ml salmon sperm DNA and 15% formamide at 68° C. For the purposes of specifying additional conditions of high stringency, preferred conditions are salt concentration of about 200 mM and temperature of about 45°C. One example of such stringent conditions is hybridization at 4XSSC, at 65°C, followed by a washing in 0.1XSSC at 65°C for one hour. Another exemplary stringent hybridization scheme uses 50% formamide, 4XSSC at 42°C. In contrast, nucleic acids having sequence similarity are detected by hybridization under lower stringency conditions. Thus, sequence identity can be determined by hybridization under lower stringency conditions, for example, at 50°C or higher and 0.1XSSC (9 mM NaCI/0.9 mM sodium citrate) and the sequences will remain bound when subjected to washing at 55°C in 1XSSC. V.E. Complementarity and Hybridization to an Engineered Tie2 or Tie2K Mutant Seguence As used herein, the term "complementary sequences" means nucleic acid sequences which are base-paired according to the standard Watson- Crick complementarity rules. The present invention also encompasses the use of nucleotide segments that are complementary to the sequences of the present invention. A particular example of a contemplated complementary nucleic acid segment is an antisense oligonucleotide. Hybridization can also be used for assessing complementary sequences and/or isolating complementary nucleotide sequences. As discussed above, nucleic acid hybridization will be affected by such conditions as salt concentration, temperature, or organic solvents, in addition to the base composition, length of the complementary strands, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. Stringent temperature conditions will generally include temperatures in excess of about 30°C, typically in excess of about 37°C, and preferably in excess of about 45°C. Stringent salt conditions will ordinarily be less than about 1,000 mM, typically less than about 500 mM, and preferably less than about 200 mM. However, the combination of parameters is much more important than the measure of any single parameter. See, e.g., Wetmur & Davidson, (1968) J. Mol. Biol. 31 : 349-70. Determining appropriate hybridization conditions to identify and/or isolate sequences containing high levels of homology is well known in the art. See, e.g., Sambrook et al., (1992) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York. V.F. Functional Equivalents of an Engineered Tie2 or Tie2K Mutant Nucleic Acid Sequence of the Present Invention As used herein, the term "functionally equivalent codon" is used to refer to codons that encode the same amino acid, such as the ACG and AGU codons for serine. Tie2 or Tie2K-encoding nucleic acid sequences comprising SEQ ID NO: 5 which have functionally equivalent codons are covered by the invention. Thus, when referring to the sequence example presented in SEQ ID NO: 5, applicants contemplate substitution of functionally equivalent codons into the sequence example of SEQ ID NO: 5. Thus, applicants are in possession of amino acid and nucleic acids sequences which include such substitutions but which are not set forth herein in their entirety for convenience. It will also be understood by those of skill in the art that amino acid and nucleic acid sequences can include additional residues, such as additional N- or C-terminal amino acids or 5' or 3' nucleic acid sequences, and yet still be essentially as set forth in one of the sequences disclosed herein, so long as the sequence retains biological protein activity where polypeptide expression is concerned. The addition of terminal sequences particularly applies to nucleic acid sequences which can, for example, include various non-coding sequences flanking either of the 5' or 3' portions of the coding region or can include various internal sequences, i.e., introns, which are known to occur within genes. V.G. Biological Eguivalents The present invention envisions and includes biological equivalents of an engineered Tie2 or Tie2K mutant polypeptide of the present invention. The term "biological equivalent" refers to proteins having amino acid sequences which are substantially identical to the amino acid sequence of an engineered Tie2K mutant of the present invention and which are capable of exerting a biological effect in that they are capable of being autophosphorylated at residue tyrosine 992, leading to an activated Tie2 or Tie2K polypeptide, or cross-reacting with anti-Tie2 or Tie2K mutant antibodies raised against an engineered mutant Tie2 or Tie2K polypeptide of the present invention. For example, certain amino acids can be substituted for other amino acids in a protein structure without appreciable loss of interactive capacity with, for example, structures in the nucleus of a cell. Since it is the interactive capacity and nature of a protein that defines that protein's biological functional activity, certain amino acid sequence substitutions can be made in a protein sequence (or the nucleic acid sequence encoding it) to obtain a protein with the same, enhanced, or antagonistic properties. Such properties can be achieved by interaction with the normal targets of the protein, but this need not be the case, and the biological activity of the invention is not limited to a particular mechanism of action. It is thus in accordance with the present invention that various changes can be made in the amino acid sequence of an engineered Tie2 or Tie2K mutant polypeptide of the present invention or its underlying nucleic acid sequence without appreciable loss of biological utility or activity. Biologically equivalent polypeptides, as used herein, are polypeptides in which certain, but not most or all, of the amino acids can be substituted. Thus, when referring to the sequence example presented in SEQ ID NO: 5, applicants envision substitution of codons that encode biologically equivalent amino acids as described herein into the sequence example of SEQ ID NO: 6. Thus, applicants are in possession of amino acid and nucleic acids sequences which include such substitutions but which are not set forth herein in their entirety for convenience. Alternatively, functionally equivalent proteins or peptides can be created via the application of recombinant DNA technology, in which changes in the protein structure can be engineered, based on considerations of the properties of the amino acids being exchanged, e.g. substitution of lie for Leu. Changes designed by man can be introduced through the application of site- directed mutagenesis techniques, e.g., to introduce improvements to the antigenicity of the protein or to test an engineered Tie2 or Tie2K mutant polypeptide of the present invention in order to modulate autophosphorylation activity, or other activity at the molecular level. Amino acid substitutions, such as those which might be employed in modifying an engineered Tie2 or Tie2K mutant polypeptide of the present invention are generally, but not necessarily, based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. An analysis of the size, shape and type of the amino acid side-chain substituents reveals that arginine, lysine and histidine are all positively charged residues; that alanine, glycine and serine are all of similar size; and that phenylalanine, tryptophan and tyrosine all have a generally similar shape. Therefore, based upon these considerations, arginine, lysine and histidine; alanine, glycine and serine; and phenylalanine, tryptophan and tyrosine; are defined herein as biologically functional equivalents. Other biologically functionally equivalent changes will be appreciated by those of skill in the art. It is implicit in the above discussion, however, that one of skill in the art can appreciate that a radical, rather than a conservative substitution is warranted in a given situation. Non-conservative substitutions in engineered mutant Tie2 or Tie2K polypeptides of the present invention, for example SEQ ID NO: 6, are, therefore, an aspect of the present invention. In making biologically functional equivalent amino acid substitutions, the hydropathic index of amino acids can be considered. Each amino acid has been assigned a hydropathic index on the basis of their hydrophobicity and charge characteristics, these are: isoleucine (+ 4.5); valine (+ 4.2); leucine (+ 3.8); phenylalanine (+ 2.8); cysteine (+ 2.5); methionine (+ 1.9); alanine (+ 1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (- 3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5). The importance of the hydropathic amino acid index in conferring interactive biological function on a protein is generally understood in the art (Kvte & Doolittle, (1982), J. Mol. Biol. 157: 105-132) incorporated herein by reference). It is known that certain amino acids can be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based upon the hydropathic index, the substitution of amino acids whose hydropathic indices are within ±2 of the original value is preferred, those which are within ±1 of the original value are particularly preferred, and those within ±0.5 of the original value are even more particularly preferred. It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Patent No. 4,554,101 , incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e. with a biological property of the protein. It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent protein. As detailed in U.S. Pat. No. 4,554,101 , the following hydrophilicity values have been assigned to amino acid residues: arginine (+ 3.0); lysine (+ 3.0); aspartate (+ 3.0±1); glutamate (+ 3.0±1); serine (+ 0.3); asparagine (+ 0.2); glutamine (+ 0.2); glycine (0); threonine (-0.4); praline (-0.5±1); alanine (- 0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (- 1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4). In making changes based upon similar hydrophilicity values, the substitution of amino acids whose hydrophilicity values are within ±2 of the original value is preferred, those which are within ±1 of the original value are particularly preferred, and those within ±0.5 of the original value are even more particularly preferred. While discussion has focused on functionally equivalent polypeptides arising from amino acid changes, it will be appreciated that these changes can be effected by alteration of the encoding DNA, taking into consideration also that the genetic code is degenerate and that two or more codons can code for the same amino acid. Thus, it will also be understood that this invention is not limited to the particular amino acid and nucleic acid sequences of SEQ ID NOs: 5 and 6. Recombinant vectors and isolated DNA segments can therefore variously include an engineered Tie2 or Tie2K mutant polypeptide-encoding region itself, include coding regions bearing selected alterations or modifications in the basic coding region, or include larger polypeptides which nevertheless comprise Tie2 or Tie2K mutant polypeptide-encoding regions or can encode biologically functional equivalent proteins or polypeptides which have variant amino acid sequences. Biological activity of an engineered Tie2 or Tie2K mutant polypeptide can be determined, for example, by phosphorylation assays known to those of skill in the art. The nucleic acid segments of the present invention, regardless of the length of the coding sequence itself, can be combined with other DNA sequences, such as promoters, enhancers, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length can vary considerably. It is therefore contemplated that a nucleic acid fragment of almost any length can be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant DNA protocol. For example, nucleic acid fragments can be prepared which include a short stretch complementary to a nucleic acid sequence set forth in SEQ ID NO: 5, such as about 10 nucleotides, and which are up to 10,000 or 5,000 base pairs in length, with segments of 3,000 being preferred in certain cases. DNA segments with total lengths of about 4,000, 3,000, 2,000, 1 ,000, 500, 200, 100, and about 50 base pairs in length are also useful. The DNA segments of the present invention encompass biologically functional equivalents of engineered Tie2 or Tie2K mutant polypeptides. Such sequences can rise as a consequence of codon redundancy and functional equivalency that are known to occur naturally within nucleic acid sequences and the proteins thus encoded. Alternatively, functionally equivalent proteins or polypeptides can be created via the application of recombinant DNA technology, in which changes in the protein structure can be engineered, based on considerations of the properties of the amino acids being exchanged. Changes can be introduced through the application of site- directed mutagenesis techniques, e.g., to introduce improvements to the antigenicity of the protein or to test variants of an engineered Tie2 or Tie2K mutant of the present invention in order to examine the degree of autophosphorylation, or other activity at the molecular level. Various site- directed mutagenesis techniques are known to those of skill in the art. The invention further encompasses fusion proteins and peptides wherein an engineered Tie2 or Tie2K mutant coding region of the present invention is aligned within the same expression unit with other proteins or peptides having desired functions, such as for purification or immunodetection purposes. Recombinant vectors form important further aspects of the present invention. Particularly useful vectors are those in which the coding portion of the DNA segment is positioned under the control of a promoter. The promoter can be that naturally associated with a Tie2 gene, as can be obtained by isolating the 5' non-coding sequences located upstream of the coding segment or exon, for example, using recombinant cloning and/or PCR technology and/or other methods known in the art, in conjunction with the compositions disclosed herein. In other embodiments, certain advantages will be gained by positioning the coding DNA segment under the control of a recombinant, or heterologous, promoter. As used herein, a recombinant or heterologous promoter is a promoter that is not normally associated with a Tie2 gene in its natural environment. Such promoters can include promoters isolated from bacterial, viral, eukaryotic, or mammalian cells. Naturally, it will be important to employ a promoter that effectively directs the expression of the DNA segment in the cell type chosen for expression. The use of promoter and cell type combinations for protein expression is generally known to those of skill in the art of molecular biology (See, e.g., Sambrook et al., 1992, specifically incorporated herein by reference). The promoters employed can be constitutive or inducible and can be used under the appropriate conditions to direct high level expression of the introduced DNA segment, such as is advantageous in the large-scale production of recombinant proteins or peptides. Appropriate promoter systems contemplated for use in high-level expression include, but are not limited to, the vaccinia virus promoter and, more preferably, a baculovirus promoter. VI. Identification of Reaction Intermediates The present invention also provides for the development of compounds that can isomerize to short-lived reaction intermediates in the chemical reaction of a substrate, or other compound that binds to Tie2 or Tie2K, or with Tie2 or Tie2K. Thus, the time-dependent analysis of structural changes in Tie2 or Tie2K during its interaction with other molecules is provided. The reaction intermediates of Tie2 or Tie2K-mediated chemical processes can also be deduced from the reaction product in co-complex with Tie2 or Tie2K. Such information is useful to design improved analogues of any known Tie2 or Tie2K modulators, or to design novel classes of modulators based on the reaction intermediates of the Tie2 or Tie2K polypeptide and the polypeptide- modulator co-complex. This provides a novel route for designing Tie2 or Tie2K modulators with both high specificity and stability. Another approach provided by the present invention, is to screen computationally small molecule databases for chemical entities or compounds that can bind in whole, or in part, to the Tie2 or Tie2K polypeptide. In this screening, the quality of fit of such entities or compounds to the binding site can be judged either by shape complementarity or by estimated interaction energy (Meng et al.. (1992) J. Comb. Chem. 13: 505-524). VIL The Role of the Three-Dimensional Structure of Tie2K in Solving Additional Tie2K Crystals Because Tie2K can crystallize in more than one crystal form (four representative forms were generated in the present invention), the structure coordinates of Tie2K, or portions thereof, as provided by the present invention are particularly useful to solve the structure of other crystal forms of Tie2K. They can also be used to solve the structure of Tie2K mutants (such as those prepared as disclosed in Section V above), Tie2K co-complexes, or of the crystalline form of any other protein with significant amino acid sequence homology to any functional domain of Tie2K. VILA. Determining the Three-Dimensional Structure of a Polypeptide Using the Three-Dimensional Structure of Tie2K as a Template in Molecular Replacement One method that can be employed for the purpose of solving additional Tie2K crystal structures, which was used to solve the three-dimensional structure of Tie2K in the present invention, is molecular replacement. In the molecular replacement method, the unknown crystal structure, whether it is another crystal form of Tie2K, i.e. a Tie2K mutant or a Tie2K polypeptide complexed with another compound (a "co-complex"), or the crystal of some other protein with significant amino acid sequence homology to any functional region of Tie2K, can be determined using the Tie2K structure coordinates provided in Tables 2-5. This method provides an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio. In addition, in accordance with this invention, Tie2K mutants can be crystallized in complex with known Tie2K modulators. The crystal structures of a series of such complexes can then be solved by molecular replacement and compared with that of wild-type Tie2K. Potential sites for modification within the various binding sites of the enzyme can thus be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions, between Tie2K and a chemical entity or compound. All of the complexes referred to in the instant disclosure can be studied using well-known X-ray diffraction techniques (See, e.g., Blundell & Johnson (1985) Methods in Enzymology, 114A & 115B, Wvckoff et al., eds., Academic Press) and can be refined using computer software, such as the X-PLOR™ program (Yale University,© 1992, available from Molecular Simulations, Inc., San Diego, California). This information can thus be used to optimize known classes of Tie2K modulators, and more importantly, to design and synthesize novel classes of Tie2K modulators. Laboratory Examples The following Laboratory Examples have been included to illustrate preferred modes of the invention. Certain aspects of the following Laboratory Examples are described in terms of techniques and procedures found or contemplated by the present inventors to work well in the practice of the invention. These Laboratory Examples are exemplified through the use of standard laboratory practices of the inventors. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following Laboratory Examples are intended to be exemplary only and that numerous changes, modifications and alterations can be employed without departing from the spirit and scope of the invention. Laboratory Example 1 Protein Expression The cytoplasmic domain of Tie2 was cloned from a human kidney cDNA library (Clontech, Palo Alto, California) by PCR. The sequence was identical to that reported in GENBANK (L06139). The coding region corresponding to residues 808-1124 was subcloned into a pFASTBACI ™ (Gibco BRL, Rockville, Maryland) expression vector by PCR. The N-terminal primer included an Sst1 restriction site and a methionine start codon followed by six histidine codons. The C-terminal primer included a stop codon and an Xhol restriction site. The PCR product was cloned into the Sst1/Xhol site of pFASTBACI ™. All restriction enzymes were from either New England Biolabs (Beverly, Massachusetts) or GibcoBRL (Rockville, Maryland) and used as suggested by the supplier. The Tie2K construct was transfected into Spodoptera frugiperda (Sf9) cells, single plaques were isolated, and high titer stocks were generated. Sf9 cells, in a 36L fermentor, were infected at a multiplicity of infection of 5 for 72 hours and harvested by centrifugation at 3000rpm for 20 minutes. Laboratory Example 2 Protein Purification Cells from 12L of culture (~200g of wet cell paste) were resuspended in 1200mL of 50 mM HEPES (pH 8), 200 mM NaCl, and 20 mM imidazole and were disrupted using a Polytron ® homogenizer (Brinkmann Instruments, Westbury, New York) and by sonication. The homogenate was centrifuged for 40 minutes at 12,500 rpm (Sorvall GSA rotor, available from Kendro Laboratory Products, Newtown, Connecticut). The supernatant was filtered (1.2 micron cartridge filter) and was loaded onto a nickel-chelating column (70mL bed volume, Chelating SEPHAROSE™ FF, Pharmacia, Peapack, New Jersey) at 20mL/min. Protein was eluted with a 10 column volume linear gradient between 20 and 300 mM imidazole in 50 mM HEPES (pH 8), 200 mM NaCl. 25mL column fractions were collected and analyzed by SDS PAGE. Tie2K protein was pooled and loaded directly onto a hydroxylapatite column having 40mL bed volume (Type I ceramic hydroxylapatite available from BioRad, Inc., of Hercules, California) at 20mL/min. A linear gradient was run from 0 to 100 mM potassium phosphate in 20 mM Tris-HCI (pH 8), 50 mM NaCl, 5 mM DTT, and 5% glycerol. 10mL column fractions were collected and analyzed by SDS PAGE. The Tie2K containing fractions were diluted 1 :1 with 20 mM Tris-HCI (pH 8), 5 mM DTT, and 5% glycerol, loaded onto an anion exchange column (35mL bed volume, Q-SEPHAROSE™ HP, Pharmacia, Peapack, New Jersey) at 10mL/min and eluted with a 0-600 mM NaCl gradient. 5mL fractions were collected and analyzed by SDS PAGE and mass spectrometry. Tie2K was pooled based upon SDS PAGE and mass spectrometry analysis (>95% purity) and stored at -80°C. Typically Tie2 eluted in 2 to 3 discrete peaks, reflecting different mixes of phosphorylation states. Laboratory Example 3 In vitro Autophosphorylation for Mass Spectrometry Wild-type and mutant Tie2K were incubated with 2 mM ATP and 10 mM MgCI 2 for 30 minutes at room temperature in 25 mM HEPES pH 7.5, 150 mM NaCl and 10 mM DTT. Samples were flash frozen in a dry ice/ethanol bath and stored at -180° C until they could be analyzed by mass spectrometry. Laboratory Example 4 In vitro Kinase Assay 10 nM non-activated or pre-activated Tie2K was used to phosphorylate 1 μM of a peptide substrate (Biotin-Ahx-LEARLVAYEGWVAGKKK-NH 2 , synthesized by SynPep Corp., Dublin, California) (SEQ ID NO: 13) in the presence of 80 μM ATP, 10 mM MgCI 2 , 1 mM DTT, 0.1 mg/ml BSA, and 0.1 M pH 7.5. The reaction was carried out at room temperature for 30 minutes, and stopped by the addition of 50 mM EDTA. 1.2 μg/ml Streptavidin-APC (Molecular Probes, Eugene, Oregon) and 0.15 μg/ml Eu-α-pY (EG&G Wallac, Gaithersburg, Maryland) in the presence of 0.1 mg/ml BSA, 0.1 M HEPES pH7.5 were added and the reactions incubated for 10 min at room temperature. Streptavidin-APC and Eu-α-pY bind to the phosphorylated peptides to form a complex, allowing fluorescent energy transfer from Eu to APC. The plate was read on a VICTOR™ plate reader (EG&G Wallac, Gaithersburg, Maryland) in time resolved fluorescence mode by exciting at 340 nm and reading the emission at 665 nm. Laboratory Example 5 Protein Digestion for Mass Spectrometry Trypsin digestions of 200-1000 picomoles of Tie2K were carried out in 50 mM Tris pH 8.5, 1 mM CaCI 2 , and 10 % acetonitrile. In some instances, Tie2K was reduced and alkylated with DTT and 4-vinylpyridine prior to digestion. Digestion proceeded at 37° C for 12-18 hours. Laboratory Example 6 Mass Spectrometry: LCMS Mass measurements of intact protein were determined using liquid chromatography mass spectrometry (LCMS). Protein samples were initially desalted on a Poros R2/H column (PerSeptive Biosystems; Framingham, Massachusetts). Effluent from the desalting column was directed to a SCIEX API III™ mass spectrometer (PE Sciex, Concord, Ontario, Canada) and spectra were acquired in positive ion mode with electrospray ionization. Intact protein mass values were obtained from the reconstructed mass spectra that were generated from the processed data. Assignment of phosphorylation states were made by identifying masses that were multiples of 80 Da higher than the expected mass of Tie2K. Laboratory Example 7 Mass Spectrometry: nanoES MS Nanoelectrospray ionization (nanoES) MS on a Q-TOF instrument from Micromass (Manchester, United Kingdom) was used to map phosphorylation sites after trypsin digestion. Sample was introduced to the MS with either static nanoES using a pulled capillary tip (Mann) or capillary LCMS/MS. The LC system was from LC Packings of San Francisco, California, and comprised the FAMOS™ autosampler and the ULTIMATE™ solvent delivery pump. Separation was carried out on a 75μm I.D. C-iβ PepMap column, also from LC Packings (San Francisco, California). The Q-TOF is capable of data dependent ion selection for collision-induced fragmentation. Two sample preparation approaches were used to map the phosphorylation sites. In the first approach, phosphorylated peptides were isolated from nonphosphorylated peptides using Ga(lll) immobilized metal affinity chromatography (IMAC). Briefly, an aliquot of the trypsin digest was acidified and loaded onto an IMAC microcolumn charged with Ga(lll). The column was then washed with 0.1 % acetic acid/ 30% acetonitrile to remove non-phosphorylated peptides. Retained peptides were then eluted with 0.2 M sodium phosphate, pH 8.2 and directly applied to a microcolumn packed with POROS™ R2/H reverse phase media, available from PerSeptive Biosystems, of Framingham, Massachusetts. Bound peptides were washed with 0.1 % formic acid and then eluted directly into a nanoelectrospray capillary tip. Static nanoESI was used to acquire MS and MS/MS spectra of the purified peptides. Phosphorylated residues were identified from MS/MS data. In a second approach, the Tie2K trypsin digest was analyzed by capillary LCMS/MS with data dependent scanning. This data file was then used to conduct a MASCOT™ protein database search (Matrix Science Ltd., London, United Kingdom) that compares uninterpreted MS/MS data to theoretical MS/MS spectra of user specified proteolytic peptides. The spectra were interpreted manually to confirm the assignment. Laboratory Example 8 Crystallization and Data Collection All four crystal forms of Tie2K were grown by the hanging drop vapor diffusion method in Linbro plates on siliconized cover slips (Hampton Research, Laguna Niguel, California). The protein (6mg/ml in 20 mM HEPES pH 7.5, 300 mM NaCl, 5 mM DTT) was mixed with an equal volume of reservoir (typically 2μL + 2μL drops) and incubated at 22°C. The reservoir (500μL) for crystal forms I and II was 2.5% PEG12000 (Fluka Chemie AG, Buchs, Switzerland), 2.5% glycerol (Gibco BRL, Rockville, Maryland), 100 mM HEPES pH 7.5 (Sigma, St. Louis, Missouri), and 10 mM spermidine (Sigma, St. Louis, Missouri). The reservoir (500μL) for crystal form III was 100 mM HEPES pH 7.5 (Sigma, St. Louis, Missouri), 100 mM KCI (Sigma, St. Louis, Missouri), and 10% isopropanol (EM Science) while the reservoir (500μL) for crystal form IV was 100 mM HEPES pH 7.5 (Sigma, St. Louis, Missouri) and 1.5 M NaCl (Sigma, St. Louis, Missouri). Crystals belonging to the four different space groups appeared within several days to several weeks and typically grew to -100x100x1 Oμm in 1-2 months. All 4 crystal forms had similar chunky plate morphologies. Glycerol was added as a cryoprotectant to a final concentration of 25%, over a period of 1 hour at 22°C, and the crystals, suspended in nylon loops on copper pins (Hampton Research, Laguna Niguel, California), were flash frozen in liquid N 2 . Data for crystal forms I, II and IV were collected at -180°C at beamline 17-ID on a MAR-CCD in the facilities of the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT) at the Advanced Photon Source (Argonne National Laboratory, Argonne, Illinois) using X-rays with a wavelength of 1.0 A. These facilities are supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology (I IT), executed through the NT's Center for Synchrotron Radiation Research and Instrumentation. In all three cases 180° of data was collected using 1° oscillations every 10 seconds. The detector was set to 150 mm. The space group was determined for each crystal form by merging the data from the first 5 oscillations using the HKL2000 software package (Otwinowski, (1993) in Proceedings of the CCP4 Study Weekend: Data Collection and Processing. (Sawyer et al., eds.), pp.56-62, SERC Daresbury Laboratory, England.), available from Nonius BN, Delft, The Netherlands. Entire data sets were processed using the HKL2000 software package (Nonius B.V., Delft, The Netherlands) (Otwinowski, (1993) in Proceedings of the CCP4 Study Weekend: Data Collection and Processing. (Sawyer et al.. eds.), pp.56-62, SERC Daresbury Laboratory, England). Data for crystal form III was collected at -180°C on an RAXIS IV image plate (Rigaku, Tokyo, Japan). The CuKα X-rays, having a wavelength of 1.54 A, were generated on a rotating anode, also available from Rigaku, (Tokyo, Japan) operating at 50 KVx100 mA. The space group was determined from a single oscillation using DENZO (HKL Research, Charlottesville, Virginia). 180° of data was collected using 1.5° oscillations every 50 min. The detector was set to 150 mm. The data were processed with DENZO™ (HKL Research, Charlottesville, Virginia) and scaled with SCALEPACK™, (Otwinowski, (1993) in Proceedings of the CCP4 Study Weekend: Data Collection and Processing. (Sawyer et al., eds.), pp.56-62, SERC Daresbury Laboratory, England.) also available from HKL Research, Charlottesville, Virginia. Laboratory Experiment 9 Structure Determination and Refinement The structure of crystal form I was solved first and subsequently used to solve the other three crystal forms. The structure was solved by molecular replacement using CNS (Brunger et al.. (1998) Ada. Crystallogr. D54: 905- 921.) and FGFR1 as a search model (molecule 1 of PDB entry 1 FGK) (Mohammadi et al.. (1996) Cell 86: 577-87.). The search model contained FGFR1 residues 464-485, 491-500, 506-578, 592-647 and 651-761. Residues not conserved between FGFR1 and Tie2 were truncated to alanine in the model. Rotation and translation searches were carried out using data between 10.0-4.0 A. For the rotation function, the real space method was used with a minimum Patterson vector length of 5 A. For the translation search, a general translation function with fastf2f2 target was used. The correct solutions were the top two peaks in both the rotation and translation functions and had correlation coefficients of 0.38 and 0.36. Rigidbody refinement of the two molecules in the asymmetric unit gave an R-factor of 49% using data from 10-4.0 A. Additional rigid body refinement, using data between 10-3.0 A, and allowing the 2 domains of the protein to refine independently, dropped the R-factor to 45%. Multiple rounds of model building and refinement were carried out using the AUTOBUILD mode of QUANTA™ (Release 4.0) and CNS, both available from Molecular Simulations, Inc., San Diego, California, using maximum likelihood targets based on the amplitudes. The electron density, generated from the rigidbody solution, allowed placement of most of the side chains from the original model. When the electron density resolution was extended to the limit of the diffraction, density for portions of the protein not included in the original model could be seen. Additional residues and water molecules were positioned manually in the electron density. Starting with these atomic coordinates, a diffraction pattern was calculated and compared to the experimental data. The difference between the calculated and experimentally determine diffraction patterns was monitored by the value of the R-factor. The refinement of the structural model necessitates adjustments of atomic positions to minimize the R-factor, where a value of about 20% is typical for a good quality protein structure. The overall structure was confirmed by a composite simulated-annealing omit map calculated with CNS. The map was generated by sequentially omitting 8% of the protein atoms, carrying out simulated annealing refinement at 1000°C and calculating a 2F 0 -F C electron density map. In the final model residues 813, 858, 860, 867, 997, 1099 and 1119 were modeled as alanine in all four crystal forms due to a lack of side chain density. Analysis of the structure with PROCHECK (Laskowski et al., (1993) J. Appl. Crystallogr. 26: 283-291) indicated that all main chain torsions fall within the allowed regions of the Ramachandran plot. For crystal forms II, III and IV, the final refined model for crystal form I was used as a search model. Molecular replacement was carried out using CNS using data between 10-4.0 A. The correlation coefficients were 0.45/0.49, 0.69, and 0.72 for crystal forms II, III and IV, respectively. The R- factor, following rigid body refinement (10-3.0 A), for the 3 molecular replacement solutions was 38%, 32% and 31%, respectively. Small differences in the positions of loops and surface exposed side chains were observed and manually rebuilt with the QUANTA™ software program. Waters were added manually. References The references listed below as well as all references cited in the specification are incorporated herein by reference to the extent that they supplement, explain, provide a background for or teach methodology, techniques and/or compositions employed herein. 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Chem. 28: 849-857 Goodsell & Olsen, (1990) Proteins 8: 195-202 Gribskov et al., (1986) Nucl. Acids. Res. 14: 6745 Heidaran, (1991 ) Mol. Cell. Biol. 11 : 134-142 Hu et al., (1994) Nature 369: 581-584 Huang et al., (1995) Oncogene 11 : 2097-2103 Hubbard, (1997) EMBO J. 16: 5572-5581 Hubbard et al., (1994) Nature 372: 746-754 Jeffrey et al., (1995) Nature 376: 313-320 Johnson et al., (1996) Ce// 85: 149-158 Jones & Dumont, (1998) Oncogene 17: 1097-1108 Jones et al., (1999) J. Biol. Chem. 274: 30896-30905 Knighton et al., (1991 ) Science 253: 407-413 Koblizek et al., (1998) Curr. Biol. 8: 529-532 Kontos et al., (1998) Mol. Cell. Biol. 18: 4131-4140 Korpelainen et al., (1999) Oncogene 18: 1-8 Kuiper et al., (1998) Pharmacol. Res. 37: 1-16 Kumar & Fidler, (1998) In Vivo 18: 27-34 Kuntz et al., (1992), J. Mol. Biol. 161 : 269-288 Kyte & Doolittle, (1982), J. Mol. Biol. 157: 105-132 Laskowski et al., (1993) J. Appl. Crystallogr. 26: 283-291 Lattman, (1985) in Methods in Enzymology, 115: 55-77 Lemmon & Schlessinger, (1994) Trends Biochem. Sci. 19: 459-463 Lin et al., (1998) Proc. Natl. Acad. Sci. USA 95: 8829-8834 Maisonpierre et al.. (1997) Science 277: 55-60 Martin, (1992) J. Med. Chem. 35: 2145-2154 McPherson et al., (1989) Preparation and Analysis of Protein Crystals, Robert E. Krieger Publishing Company, Malabar, Fla. McTigue et al., (1999) Structure 7: 319-330 Meng et al.. (1992) J. Comb. Chem. 13: 505-524 Merenmies et al., (1997) Cell Growth Differ. 8: 3-10 Miranker & Karplus, (1991 ) Prof e/ns 11 : 29-34 Mohammadi et al., (1996) Ce// 86: 577-87 Navia & Murcko, (1992) Current Opinions in Structural Biology 2: 202-210 Needleman et al., (1970) J. Mol. Biol. 48: 443 Nicholls et al., (1988) Proteins 11 : 281-296 Nishibata & Itai, (1991 ) Tetrahedron 47: 8985 Otwinowski, (1993) in Proceedings of the CCP4 Study Weekend: Data Collection and Processing. (Sawyer et al., eds.), pp.56-62, SERC Daresbury Laboratory, England Pepper, (1996) Vase. Med. 1 : 259-266 Risau, (1995) FASAB J. 9: 926-933 Rossmann, ed., (1972) Int. Sci. Rev. Ser., No. 13, Gordon & Breach, New York Sambrook et al.. (1992) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York Sato et aL, (1995) Nature (London) 376: 70-74 Schwartz et al., eds., (1979^) Atlas of Protein Seguence and Structure, National Biomedical Research Foundation, pp. 357-358 Smith et al., (1981 ) Adv. Appl. Math. 2:482 Suri et al.. (1996) Cell 87, 1171-1180 Suri et al., (1998) Science 282: 468-471 Szekanecz et al., (1998) J. Investig. Med. 46: 27-41 Tallquist et al., (1999) Oncogene 18: 7917-7932 Taylor et al., (1989) EMBO J. 8: 2029-2037 Tolentino & Adamis, (1988) Int. Ophthalmol. Clin. 38: 77-94 Valenzuela et al., (1999) Proc. Natl. Acad. Sci. USA 96: 1904-1909 Van Holde, (1971 ) Physical Biochemistry, Prentice-Hall, N. J., 221-239 Vikkula et al., (1996) Ce// 87: 1181-1190 Weber, (1991 ) Advances in Protein Chemistry 41 :1 -36 Wellner, (1971 ) Analyt. Chem. 43: 597 Wetmur & Davidson, (1968) J. Mol. Biol. 31 : 349-70 Witzenbichler et al., (1998) J. Biol. Chem. 273: 18514-18521 Zhang et al., (1994) Nature 367:704-711 Ziegler et al., (1993) Oncogene 8: 663-670 U.S. Patent No. 4,554,101 U.S. Patent No. 4,672,108 U.S. Patent No. 4,833,233 U.S. Patent No. 5,834,228 U.S. Patent No. 5,872,011 U.S. Patent No. 6,008,033 WO 84/03564 TABLE 1 CRYSTAL AND DATA STATISTICS Crystal Form - 111 IV Space Group P2, P2,2,2, P2,2 t 2ι C222 ! Unit cell a (A) 66 79 52 95 Unit cell b (A) 92 92 77 114 Unit cell c (A) 70 109 79 78 Unit cell β (°) 108 90 90 90 Mol asu 2 2 1 1 Resolution (A) 2.2 2.5 2.2 2.1 iV. e (%) 7.5 11 7.9 7.8 Completeness (%) 96 • 98 99 98 Rαys 'CK) 19 21 20 21 Rr«» c (%) 23 26 23 24 Number of non-hydrogen 4766 4766 2368 2375 protein atoms Number of solvent molecules 361 • 188 170 200 RMS deviations from ideal Bond lengths (A) 0.0058 0.0063 0.0064 0.0060 Bond angles (°) 1.15 1.16 1J9 1J5 *R-vm = wall - <I>| π, where I is the observed intensity and <I> is the average intensity from observations of symmetry-related reflections. b «y r t = h a (( F ob * I - 1 F ca ic || / { Fo b , I, where F ote and F^ are the observed and calculated structure factor amplitudes, respectively, for the hkl reflections. "Ri t a, is calculated for a set of reflections that were not included in atomic refinement. TABLE 2 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR T1E2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 2 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 1 TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 11 TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FORT1E2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 3 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM II TABLE 4 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM III TABLE 4 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM III TABLE 4 STRUCTURE COORDINATES FORT1E2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM III TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM III TABLE 4 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM 111 TABLE 4 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM III TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM III TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM III TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM TABLE 4 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM III TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR T1E2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FOR TIE2K CRYSTAL FORM IV TABLE 5 STRUCTURE COORDINATES FORTIE2K CRYSTAL FORM IV TABLE 6 FGFR1 COORDINATE DATA FOR RESIDUES 464-485 TABLE 6 FGFR1 COORDINATE DATA FOR RESIDUES 464-485 TABLE 6 FGFR1 COORDINATE DATA FOR RESIDUES 464-485 TABLE 6 FGFR1 COORDINATE DATA FOR RESIDUES 464-485 TABLE 6 FGFR1 COORDINATE DATA FOR RESIDUES 464-485 TABLE 7 FGFR1 COORDINATE DATA FOR RESIDUES 491-500 TABLE 7 FGFR1 COORDINATE DATA FOR RESIDUES 491-500 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 8 FGFR1 COORDINATE DATA FOR RESIDUES 506-578 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 9 FGFR1 COORDINATE DATA FOR RESIDUES 592-647 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 TABLE 10 FGFR1 COORDINATE DATA FOR RESIDUES 651-761 It will be understood that various details of the invention can be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation-- the invention being defined by the claims.

Claims: CLAIMS What is claimed is: 1. A composition comprising a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide in monoclinic crystalline form. 2. The composition of claim 1 , wherein the crystalline form has lattice constants of a = 66 A, b = 92 A, c = 70 A, α = 90°, β = 108°, γ= 90°. 3. The composition of claim 1 or 2, wherein the crystalline form has a space group of P2ι. 4. The composition of claim 1 or 2, wherein the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide has the amino acid sequence shown in SEQ ID NO: 4. 5. The composition of claim 1 or 2, wherein the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide is unphosphorylated. 6. The composition of claim 1 or 2, wherein the Tie2K receptor tyrosine kinase domain has a crystalline structure further characterized by the coordinates corresponding to Table 2. 7. The composition of claim 1 or 2, wherein the crystalline form contains two molecules in the asymmetric unit. 8. The composition of claim 1 or 2, wherein the crystalline form is such that the three-dimensional structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide can be determined to a resolution of about 2.2 A or better. 9. The composition of claim 1 , wherein the crystalline form has lattice constants of a = 79 A, b = 92 A, c = 109 A, α = 90°, β = 90°, v = 90°. 10. The composition of claim 1 , wherein the crystalline form has lattice constants of a = 52 A, b = 77 A, c = 79 A, α = 90°, β = 90°, y = 90°. 1. The composition of claim 1 , 9 or 10, wherein the crystalline form has a space group of P2-|2ι2-|. 12. The composition of claim 1 , 9 or 10, wherein the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide has the amino acid sequence shown in SEQ ID NO: 4. 13. The composition of claim 1 or 9, wherein the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide is unphosphorylated. 14. The composition of claim 1 or 10, wherein the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide is monophosphorylated. 15. The composition of claim 1 or 9, wherein the Tie2K receptor tyrosine kinase domain has a crystalline structure further characterized by the coordinates corresponding to Table 3. 16. The composition of claim 1 or 10, wherein the Tie2K receptor tyrosine kinase domain has a crystalline structure further characterized by the coordinates corresponding to Table 4. 17. The composition of claims 1 or 9, wherein the crystalline form contains two molecules in the asymmetric unit. 18. The composition of claims 1 or 10, wherein the crystalline form contains one molecule in the asymmetric unit. 19. The composition of claim 1 or 9, wherein the crystalline form is such that the three-dimensional structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide can be determined to a resolution of about 2.5 A or better. 20. The composition of claim 1 or 10, wherein the crystalline form is such that the three-dimensional structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide can be determined to a resolution of about 2.2 A or better. 21. A composition comprising cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide in orthorhombic crystalline form. 22. The composition of claim 21 wherein the crystalline form has lattice constants of a = 95 A, b = 114 A, c = 78 A, α= 90°, β = 90°, y = 90°. 23. The composition of claim 21 or 22 wherein the cytoplasmic Tie2 receptor tyrosine kinase has the amino acid sequence shown in SEQ ID NO: 6. 24. The composition of claim 21 or 22, wherein the crystalline form has a space group of C222ι. 25. The composition of claim 21 or 22 wherein the Tie2 receptor tyrosine kinase domain polypeptide is unphosphorylated. 26. The composition of claim 21 or 22, wherein the Tie2K receptor tyrosine kinase domain has a crystalline structure further characterized by the coordinates corresponding to Table 5. 27. The composition of claim 22, wherein the crystalline form is such that the three-dimensional structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide can be determined to a resolution of about 2.1 A or better. 28. A method for determining the three-dimensional structure of a crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide to a resolution of about 2.2 A or better comprising: (a) crystallizing the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; and (b) analyzing the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide to determine the three-dimensional structure of the crystallized Tie2 receptor tyrosine kinase domain polypeptide. 29. The method of claim 28, wherein the analyzing is by X-ray diffraction. 30. The method of claim 28, wherein the crystallization is accomplished using the hanging drop vapor diffusion method, wherein the cytoplasmic Tie2 receptor tyrosine kinase domain is mixed with an equal volume of reservoir. 31. The method of claim 30, wherein the reservoir comprises 2.5% PEG 1200, 2.5% glycerol, 100 mM HEPES at ph 7.5 and 10 mM spermidine. 32. The method of claim 30, wherein the reservoir comprises 100 mM HEPES at pH 7.5, 100 mM KCI and 10% isopropanol. 33. The method of claim 30, wherein the reservoir comprises 100 mM HEPES at pH 7.5 and 1.5 M NaCl. 34. A crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide produced by the method of claim 30. 35. A method of designing a modulator of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide, the method comprising: (a) designing a potential modulator of the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide that will form bonds with amino acids in a substrate binding site based upon a crystalline structure of the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; (b) synthesizing the modulator; and (c) determining whether the potential modulator modulates the activity of the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide. 36. A method of designing a modulator of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide the method comprising: (a) obtaining a monoclinic or orthorhombic crystal of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; (b) evaluating the three-dimensional structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; and (c) synthesizing a potential modulator based on the three- dimensional crystal structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide. 37. The method of claim 36, further comprising contacting a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide with the potential modulator; and assaying the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide for binding of the potential modulator, for a change in activity of the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide, or both. 38. The method of claim 36, wherein the crystals are such that the three-dimensional structure of the crystallized cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide can be determined to a resolution of about 2.2 A or better. 39. A method of screening for a modulator of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide, the method comprising: (a) providing a library of test samples; (b) contacting a crystalline form of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide with each test sample; (c) detecting an interaction between a test sample and the crystalline form of cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; (d) identifying a test sample that interacts with the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide; and (e) isolating a test sample that interacts with the cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide. 40. The method of claim 39, wherein the test samples are bound to a substrate. 41. The method of claim 39, wherein the test samples are synthesized directly on a substrate. 42. A cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide having at least one mutation in the amino acid sequence of the polypeptide, wherein the mutation is selected from the group consisting of Y897F, Y1048F or S1119A. 43. An isolated and substantially pure nucleic acid sequence encoding a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide of claim 42. 44. An isolated and substantially pure nucleic acid sequence encoding a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide of claim 42, wherein the nucleic acid sequence comprises the sequence shown in SEQ ID NO: 5. 45. An isolated and substantially pure nucleic acid sequence encoding a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide of claim 42, wherein the nucleic acid sequence comprises a sequence having at least 70% sequence identity with the nucleic acid sequence shown in SEQ ID NO: 5. 46. A nucleic acid sequence which hybridizes to and is at least 70% complementary to the nucleic acid sequence of claim 43. 47. The nucleic acid sequence of claim 46, wherein hybridization conditions comprise 6X SSC; 0.2% polyvinylpyrrolidone; 0.2% Ficoll; 0.2% bovine serum albumin; 0.1 % sodium dodecyl sulfate; 100 :gram/ml salmon sperm DNA and 15% formamide at 68° C. 48. A recombinant vector comprising a nucleic acid sequence of claim 43. 49. The recombinant vector of claim 48, further comprising: (a) a sequence of genomic viral DNA showing affinity for host cells and possessing the ability to infect said host cells; (b) a segment of DNA having the nucleic acid sequence shown in SEQ ID NO: 5 operatively linked to the sequence of genomic viral DNA, wherein the operatively-linked nucleic acid sequence shown in SEQ ID NO: 5 is expressed in said host cell following infection of the cell; and (c) a selectable marker. 50. A substantially pure preparation of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide of claim 42, wherein the polypeptide has the amino acid sequence shown in SEQ ID NO: 6. 51. A substantially pure preparation of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide of claim 42, wherein the polypeptide has at least 70% sequence identity with the amino acid sequence shown in SEQ ID NO: 6. 52. The substantially pure preparation of a cytoplasmic Tie2 receptor tyrosine kinase domain polypeptide of claim 50 or claim 51 , wherein the polypeptide has autophosphorylation activity.

Inventors: DAVIS RODERICK GERALD, ELLIS BYRON PETERS, HASSELL ANNE MOORE, HOLMES WILLIAM D, SHEWCHUK LISA MARIE, DAVIS, RODERICK, GERALD, ELLIS, BYRON, PETERS, HASSELL, ANNE, MOORE, HOLMES, WILLIAM, D, SHEWCHUK, LISA, MARIE
Applicants: DAVIS RODERICK GERALD, ELLIS BYRON PETERS, GLAXO GROUP LTD, HASSELL ANNE MOORE, HOLMES WILLIAM D, SHEWCHUK LISA MARIE, DAVIS, RODERICK, GERALD, ELLIS, BYRON, PETERS, GLAXO GROUP LIMITED, HASSELL, ANNE, MOORE, HOLMES, WILLIAM, D, SHEWCHUK, LISA, MARIE
Application year: 2001
Main classification: C12N9
IPC codes: C07K14