1818 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 4 (29) Hirsila, M.; Koivunen, P.; Gunzler, V.; Kivirikko, K. I.; Mylly- harju, J. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem. 2003, 278 (33), 30772–30780. (30) Mole, D. R.; Schlemminger, I.; McNeill, L. A.; Hewitson, K. S.; Pugh, C. W.; Ratcliffe, P. J.; Schofield, C. J. 2-Oxoglutarate analogue inhibitors of HIF prolyl hydroxylase. Bioorg. Med. Chem. Lett. 2003, 13 (16), 2677–2680. (31) Jaakkola, P.; Mole, D. R.; Tian, Y. M.; Wilson, M. I.; Gielbert, J.; Gaskell, S. J.; Kriegsheim, A.; Hebestreit, H. F.; Mukherji, M.; Schofield, C. J.; Maxwell, P. H.; Pugh, C. W.; Ratcliffe, P. J. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001, 292 (5516), 468–472. (32) Chowdhury, R.; McDonough, M. A.; Mecinovic, J.; Loenarz, C.; Flashman, E.; Hewitson, K. S.; Domene, C.; Schofield, C. J. Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. Structure 2009, 17 (7), 981– 989. (33) McDonough, M. A.; Li, V.; Flashman, E.; Chowdhury, R.; Mohr, C.; Lienard, B. M.; Zondlo, J.; Oldham, N. J.; Clifton, I. J.; Lewis, Rose et al. J.; McNeill, L. A.; Kurzeja, R. J.; Hewitson, K. S.; Yang, E.; Jordan, S.; Syed, R. S.; Schofield, C. J. Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc. Natl. Acad. Sci. U.S.A 2006, 103 (26), 9814–9819. (34) Hewitson, K. S.; Holmes, S. L.; Ehrismann, D.; Hardy, A. P.; Chowdhury, R.; Schofield, C. J.; McDonough, M. A. Evidence that two enzyme-derived histidine ligands are sufficient for iron binding and catalysis by factor inhibiting HIF (FIH). J. Biol. Chem. 2008, 283 (38), 25971–25978. (35) Loenarz, C.; Schofield, C. J. Expanding chemical biology of 2-oxoglutarate oxygenases. Nat. Chem. Biol. 2008, 4 (3), 152–156. (36) Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1994, 50, 760-763. (37) Emsley, P.; Cowtan, K. Acta Crystallogr., Sect. D: Biol. Crystal- logr. 2004, 60, 2126–2132. (38) Davis, I. W.; Leaver-Fay, A.; Chen, V. B.; Block, J. N.; Kapral, G. J.; Wang, X.; Murray, L. W.; Arendall, W. B., III; Snoeyink, J.; Richardson, J. S.; Richardson, D. C. MolProbity: all-atom con- tacts and structure validation for proteins and nucleic acids. Nucleic Acids Res. 2007, 35 (Web Server Issue), W375–W383.