SII-SWORD/CoKE huggingface dataset:
14-3-3 protein (14-3-3)
Type: Family

The 14-3-3 proteins are a large family of approximately 30kDa acidic proteins which exist primarily as homo- and heterodimers within all eukaryotic cells . These are structurally similar phospho-binding proteins that regulate multiple signaling pathways . There is a high degree of sequence identity and conservation between all the 14-3-3 isotypes, particularly in the regions which form the dimer interface or line the central ligand binding channel of the dimeric molecule. Each 14-3-3 protein sequence can be roughly divided into three sections: a divergent amino terminus, the conserved core region and a divergent carboxyl terminus. The conserved middle core region of the 14-3-3s encodes an amphipathic groove that forms the main functional domain, a cradle for interacting with client proteins. The monomer consists of nine helices organised in an antiparallel manner, forming an L-shaped structure. The interior of the L-structure is composed of four helices: H3 and H5, which contain many charged and polar amino acids, and H7 and H9, which contain hydrophobic amino acids. These four helices form the concave amphipathic groove that interacts with target peptides.

The 14-3-3 proteins mainly bind proteins containing phosphothreonine or phosphoserine motifs, however exceptions to this rule do exist. Extensive investigation of the 14-3-3 binding site of the mammalian serine/threonine kinase Raf-1 has produced a consensus sequence for 14-3-3-binding, RSxpSxP (in the single-letter amino-acid code, where x denotes any amino acid and p indicates that the next residue is phosphorylated). The 14-3-3 proteins appear to effect intracellular signalling in one of three ways - by direct regulation of the catalytic activity of the bound protein, by regulating interactions between the bound protein and other molecules in the cell by sequestration or modification or by controlling the subcellular localisation of the bound ligand. Proteins appear to initially bind to a single dominant site and then subsequently to many, much weaker secondary interaction sites. The 14-3-3 dimer is capable of changing the conformation of its bound ligand whilst itself undergoing minimal structural alteration.
Orn/Lys/Arg decarboxylase, major domain (Orn/Lys/Arg_deCO2ase_major_dom)
Type: Domain

Pyridoxal-dependent decarboxylases are bacterial proteins acting on ornithine, lysine, arginine and related substrates . One of the regions of sequence similarity contains a conserved lysine residue, which is the site of attachment of the pyridoxal-phosphate group. Ornithine decarboxylase is a dodecamer composed of six homodimers and catalyzes the decarboxylation of tryptophan. Arginine decarboxylase catalyzes the decarboxylation of arginine and lysine decarboxylase catalyzes the decarboxylation of lysine. Members of this family are widely found in all three forms of life .
Glycosyl transferase, family 3 (Glycosyl_Trfase_fam3)
Type: Domain

The glycosyl transferase family includes anthranilate phosphoribosyltransferase (TrpD,

) and thymidine phosphorylase (

). All these proteins can transfer a phosphorylated ribose substrate. Thymidine phosphorylase (

) catalyses the reversible phosphorolysis of thymidine, deoxyuridine and their analogues to their respective bases and 2-deoxyribose 1-phosphate. This enzyme regulates the availability of thymidine and is therefore essential to nucleic acid metabolism.
PWWP domain (PWWP_dom)
Type: Domain

The PWWP domain is an around 70 amino acids domain that was named after its central core 'Pro-Trp-Trp-Pro'. The PWWP domain is found in one or, less frequently, in two copies in nuclear, often DNA-binding proteins that function as transcription factors regulating developmental processes. Due to its position, the composition of amino acids close to the PWWP motif and the pattern of other domains present, it has been proposed that the PWWP domain is involved in protein-protein interactions . The structure of the PWWP domain comprises a five-stranded β-barrel followed by a five-helix bundle .

Conservation of the PWWP domain is concentrated on one major and two minor blocks with length differences occurring in between .
Gastrin receptor (Gastrin_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Gastrins and cholecystokinins (CCKs) are naturally-occurring peptides that share a common C-terminal sequence, GWMDF; full biological activity resides in this region. The principal physiological role of gastrin is to stimulate acid secretion in the stomach; it also has trophic effects on gastric mucosa. Gastrin is produced from a single gene transcript, and is found predominantly in the stomach and intestine, but also in vagal nerves. The CCKB receptor has a widespread distribution in the CNS and has been implicated in the pathogenesis of panic-anxiety attacks caused by CCK-related peptides. It has a more limited distribution in the periphery, where it is found in smooth muscle and secretory glands.
B-box-type zinc finger (Znf_B-box)
Type: Domain

This entry represents B-box-type zinc finger domains, which are around 40 residues in length.

B-box zinc fingers can be divided into two groups, where types 1 and 2 B-box domains differ in their consensus sequence and in the spacing of the 7-8 zinc-binding residues. Several proteins contain both types 1 and 2 B-boxes, suggesting some level of cooperativity between these two domains. B-box domains are found in over 1500 proteins from a variety of organisms. They are found in TRIM (tripartite motif) proteins that consist of an N-terminal RING finger (originally called an A-box), followed by 1-2 B-box domains and a coiled-coil domain (also called RBCC for Ring, B-box, Coiled-Coil). TRIM proteins contain a type 2 B-box domain, and may also contain a type 1 B-box. In proteins that do not contain RING or coiled-coil domains, the B-box domain is primarily type 2. Many type 2 B-box proteins are involved in ubiquitination. Proteins containing a B-box zinc finger domain include transcription factors, ribonucleoproteins and proto-oncoproteins; for example, MID1, MID2, TRIM9, TNL, TRIM36, TRIM63, TRIFIC, NCL1 and CONSTANS-like proteins .

The microtubule-associated E3 ligase MID1 (

) contains a type 1 B-box zinc finger domain. MID1 specifically binds Alpha-4, which in turn recruits the catalytic subunit of phosphatase 2A (PP2Ac). This complex is required for targeting of PP2Ac for proteasome-mediated degradation. The MID1 B-box coordinates two zinc ions and adopts a β/β/α cross-brace structure similar to that of ZZ, PHD, RING and FYVE zinc fingers .
Plant EC metallothionein-like protein, family 15 (Metallthion_15)
Type: Family

Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds . An empirical classification into three classes has been proposed by Fowler and coworkers and Kojima . Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as MTs from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins, fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units .
This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Consequently, all class I and class II MTs (the proteinaceous sequences) have now been grouped into families of phylogenetically-related and thus alignable sequences. This system subdivides the MT superfamily into families, subfamilies, subgroups, and isolated isoforms and alleles.
The metallothionein superfamily comprises all polypeptides that resemble equine renal metallothionein in several respects : e.g., low molecular weight; high metal content; amino acid composition with high Cys and low aromatic residue content; unique sequence with characteristic distribution of cysteines, and spectroscopic manifestations indicative of metal thiolate clusters. A MT family subsumes MTs that share particular sequence-specific features and are thought to be evolutionarily related. The inclusion of a MT within a family presupposes that its amino acid sequence is alignable with that of all members. Fifteen MT families have been characterised, each family being identified by its number and its taxonomic range: e.g., Family 1: vertebrate MTs.

Family 15 consists of planta MTs. Its members are recognised by the sequence pattern [YFH]-x(5,25)-C-[SKD]-C-[GA]-[SDPAT]-x(0,1)-C-x-[CYF] which yields all plant sequences, but also MTCU_HELPO and the non-MT ITB3_HUMAN. The taxonomic range of the members extends to planta. Planta MTs are 45-84 residue proteins, containing 17 conserved cysteines that bind 5 zinc ions. Generally, there are two Cys-rich regions (domain 1 and domain 3) separated by a Cys-poor region (domain 2) and only the domain 2 contains unusual residues. It is believed that the proteins may have a role in Zn
2+
homeostasis during embryogenesis. Family 15 includes the following subfamilies: p1, p2, p2v, p3, pec, p21.
Nitrogenase component 1, conserved site (Nase_comp1_CS)
Type: Conserved_site

Nitrogenase (

) is the enzyme system responsible for biological nitrogen fixation. Nitrogenase is an oligomeric complex which consists of two components: component 2 is an homodimer of an iron-sulphur protein, while component 1 which contains the active site for the reduction of nitrogen to ammonia exists in three different forms: the molybdenum-iron containing protein (MoFe) is a hetero-tetramer consisting of two pairs of alpha (nifD) and beta (nifK) subunits; the vanadium-iron containing protein (VFe) is a hexamer of two pairs each of alpha (vnfD), beta (vnfK), and delta (vnfG) subunits; the third form seems to only contain iron and is a hexamer composed of alpha (anfD), beta (anfK), and delta (anfG) subunits. The alpha and beta chains of the three types of component 1 are evolutionary related and they are also related to proteins nifE and nifN, which are most probably involved in the iron-molybdenum cofactor biosynthesis .
Aspartate-semialdehyde dehydrogenase, conserved site (Asp-semialdehyde_DH_CS)
Type: Conserved_site

Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids -lysine, threonine, methionine and isoleucine -in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see .

Aspartate-semialdehyde dehydrogenase (

), the second enzyme in the aspartate pathway, converts aspartyl phosphate to aspartate-semialdehyde, the branch point intermediate between the lysine and threonine/methionine pathways. Based on sequence alignments, the aspartate-semialdehyde dehydrogenase family appears to have at least three distinct subfamilies. Most studies have been performed on enzymes isolated from Gram-negative bacteria . The N-terminal domain forms the active site and NADP-binding pocket, while C-terminal domain is primarily involved in hydrophobic intersubunit contacts. The catalytic mechanism involves the formation of a covalent thioester acyl-enzyme intermediate mediated through nucleophilic attack by an active site cysteine residue on the substrate aspartyl phosphate. Release of inorganic phosphate is followed by hydride transfer from NADPH to yield the product. The recently described archaeal structure suggests that the two subgroups of aspartate semi-aldehyde dehydrogenase share similar structures and have an identical catalytic mechanism, despite their relatively low sequence identity . Unlike the bacterial enzymes, the archaeal enzyme utilised both NAD and NADP as cofactor.

This entry represents a conserved region found in both branches of aspartate-semialdehyde dehydrogenase family.
Hedgehog, N-terminal signalling domain (Hedgehog_signalling_dom)
Type: Domain

Hedgehog proteins are a family of secreted signal molecules required for embryonic cell differentiation. They are synthesised as inactive precursors with an N-terminal signalling domain linked to a C-terminal autoprocessing domain. The three-dimensional structure of the autolytic domain of the hedgehog protein of shows similarity with the β-strand core of intein splicing domains. It has hence been termed the hint (Hedgehog/Intein) domain .

This entry represents the N-terminal domain of hedgehog proteins, which is responsible for signalling following cleavage from the C-terminal domain. Its structure has been solved, and reveals a tetrahedrally coordinated zinc ion that appears to be structurally analogous to the zinc coordination sites of zinc hydrolases, such as thermolysin and carboxypeptidase A . This putative catalytic site represents a distinct activity from the autoprocessing activity that resides in the carboxy-terminal domain.
Delta opioid receptor (Delta_opi_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

The term opioid refers to a class of substance that produces its effects via the major classes of opioid receptor, termed mu, delta and kappa. The delta opioid receptor has a more discrete distribution in the CNS relative to the mu and kappa opioid receptors: it is found in the cerebral cortex, amygdala, nucleus accumbens, olfactory tubercle and pontine nucleus. It is also found in certain smooth muscles, e.g. hamster vas deferens, and in cell lines. Delta-receptors mediate analgesia.
Glycoside hydrolase family 31, TIM barrel domain (Glyco_hydro_31_TIM)
Type: Domain

This entry corresponds to the second domain of family 31 enzymes and adopts a TIM-barrel fold.

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glycoside hydrolase family 31

comprises enzymes with several known activities; alpha-glucosidase (

), alpha-galactosidase (

); glucoamylase (

), sucrase-isomaltase (

); isomaltase (

); alpha-xylosidase (

); alpha-glucan lyase (

).
Copper type II, ascorbate-dependent monooxygenase, N-terminal (Cu2_ascorb_mOase_N)
Type: Domain

Copper type II, ascorbate-dependent monooxygenases are a class of enzymes that requires copper as a cofactor and which uses ascorbate as an electron donor. This family contains two related enzymes, dopamine-beta-monooxygenase (

) and peptidyl-glycine alpha-amidating monooxygenase (

). There are a few regions of sequence similarities between these two enzymes, two of these regions contain clusters of conserved histidine residues which are most probably involved in binding copper.
Phosphatidic acid phosphatase type 2/haloperoxidase (PAP2/HPO)
Type: Domain

This entry represents type 2 phosphatidic acid phosphatase (PAP2;

) enzymes, such as phosphatidylglycerophosphatase B

from Escherichia coli. PAP2 enzymes have a core structure consisting of a 5-helical bundle, where the beginning of the third helix binds the cofactor . PAP2 enzymes catalyse the dephosphorylation of phosphatidate, yielding diacylglycerol and inorganic phosphate . In eukaryotic cells, PAP activity has a central role in the synthesis of phospholipids and triacylglycerol through its product diacylglycerol, and it also generates and/or degrades lipid-signalling molecules that are related to phosphatidate.

Other related enzymes have a similar core structure, including haloperoxidases (HPO) such as bromoperoxidase (contains one core bundle, but forms a dimer), chloroperoxidases (contains two core bundles arranged as in other family dimers), bacitracin transport permease from Bacillus licheniformis, glucose-6-phosphatase from rat. The vanadium-dependent haloperoxidases exclusively catalyse the oxidation of halides, and act as histidine phosphatases, using histidine for the nucleophilic attack in the first step of the reaction . Amino acid residues involved in binding phosphate/vanadate are conserved between the two families, supporting a proposal that vanadium passes through a tetrahedral intermediate during the reaction mechanism.
POU-specific domain (POU_dom)
Type: Domain

This entry represents the POU-specific subunit of the POU domain.
The POU domain is a bipartite domain composed of two subunits separated by a non-conserved region of 15-55 aa. The N-terminal subunit is known as the POU-specific (POUs) domain (this entry), while the C-terminal subunit is a homeobox domain (

). Both subdomains contain the structural motif 'helix-turn-helix', which directly associates with the two components of bipartite DNA binding sites, and both are required for high affinity sequence-specific DNA-binding. 3D structures of complexes including both POU subdomains bound to DNA are available. The domain may also be involved in protein-protein interactions . The subdomains are connected by a flexible linker . Despite of the lack of sequence homology, the tridimensional structure of POUs is similar to 3D structure of bacteriophage lambda repressor and other members of HTH_3 family .

POU proteins are eukaryotic transcription factors containing a bipartite DNA binding domain referred to as the POU domain. The acronym POU (pronounced 'pow') is derived from the names of three mammalian transcription factors, the pituitary-specific Pit-1, the octamer-binding proteins Oct-1 and Oct-2, and the neural Unc-86 from Caenorhabditis elegans. POU domain genes have been identified in diverse organisms including nematodes, flies, amphibians, fish and mammals but have not been yet identified in plants and fungi. The various members of the POU family have a wide variety of functions, all of which are related to the function of the neuroendocrine system and the development of an organism . Some other genes are also regulated, including those for immunoglobulin light and heavy chains (Oct-2) , and trophic hormone genes, such as those for prolactin and growth hormone (Pit-1).
Retroviral envelope protein GP41-like (GP41-like)
Type: Domain

This entry represents envelope proteins from a variety of retroviruses. It includes the GP41 subunit of the envelope protein complex from Human immunodeficiency virus (HIV) and Simian-Human immunodeficiency virus (SIV), which mediate membrane fusion during viral entry . It has a core composed of a six-helix bundle and is folded by its trimeric N- and C-terminal heptad-repeats (NHR and CHR) . Derivatives of this protein prevent HIV-1 from entering cell lines and primary human CD4+ cells in vitro , making it an attractive subject of gene therapy studies against HIV and related retroviruses.

The entry also represents envelope proteins from Bovine immunodeficiency virus, Feline immunodeficiency virus and Equine infectious anemia virus (EIAV) , as well as the Gp36 protein from Mouse mammary tumor virus (MMTV) and Human endogenous retrovirus (HERV).