Crystal structure of human cytochrome P450 2C9 with bound warfarin

Nature

Volumn 424, Issue 6947, 2003, Pages 464-468

  Williams, Pamela A ^a   Cosme, Jose ^a   Ward, Alison ^a   Angove, Hayley C ^a   Vinković, Dijana Matak ^a   Jhoti, Harren ^a  

^a ASTEX PHARMACEUTICALS   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CELL MEMBRANES; CRYSTAL STRUCTURE; DRUG PRODUCTS; METABOLISM; MICROORGANISMS; PLANTS (BOTANY);

HUMAN CYTOCHROMES;

PROTEINS;

CYTOCHROME P450 1A2; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; WARFARIN;

MEDICINE;

ARTICLE; CRYSTAL STRUCTURE; ENZYME CONFORMATION; ENZYME SUBSTRATE COMPLEX; HUMAN; LIGAND BINDING; MOLECULAR RECOGNITION; PRIORITY JOURNAL; XENOBIOTIC METABOLISM;

ANTICOAGULANTS; ARYL HYDROCARBON HYDROXYLASES; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; HUMANS; LIGANDS; MODELS, MOLECULAR; PROTEIN STRUCTURE, TERTIARY; WARFARIN;

ANIMALIA; MAMMALIA;

EID: 0042265520     PISSN: 00280836     EISSN: None     Source Type: Journal    
DOI: 10.1038/nature01862     Document Type: Article

References (30)

1. Anzenbacher, P. & Anzenbacherova, E. Cytochromes P450 and metabolism of xenobiotics. Cell. Mol. Life Sci. 58, 737-747 (2001).
2. Hodgson, J. ADMET-turning chemicals into drugs. Nature Biotechnol. 19, 722-726 (2001).
3. Li, H. & Poulos, T. L. conformational dynamics in cytochromeP450-substrate interactions. Biochimie 78, 695-699 (1996).
4. Li, H. & Poulos, T. L. The structure of the cytochrome P450BM-3 haem domain complexed with the fatty acid substrate, palmitoleic acid. Nature Struct. Biol. 4, 140-146 (1997).
5. Schlichting, I., Jung, C. & Schulze, H. Crystal structure of cytochrome P-450cam complexed with the (1S)-camphor enantiomer. FEBS Lett. 415, 253-257 (1997).
6. Podust, L. M., Poulos, T. L. & Waterman, M. R. Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc. Natl Acad. Sci. USA 98, 3068-3073 (2001).
7. Williams, P. A., Cosme, J., Sridhar, V., Johnson, E. F. & McRee, D. E. Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. Mol. Cell 5, 121-131 (2000).
8. Ibeanu, G. C. et al. Identification of residues 99, 220, and 221 of human cytochrome P450 2C19 as key determinants of omeprazole activity. J. Biol. Chem. 271, 12496-12501 (1996).
9. Melet, A. et al. Substrate selectivity of human cytochrome P450 2C9: importance of residues 476, 365, and 114 in recognition of diclofenac and sulfaphenazole and in mechanism-based inactivation by tienilic acid. Arch. Biochem. Biophys. 409, 80-91 (2003).
10. Haines, D. C., Tomchick, D. R., Machius, M. & Peterson, J. A. Pivotal role of water in the mechanism of P450BM-3. Biochemistry 40, 13456-13465 (2001).
11. Ridderstrom, M. et al. Arginines 97 and 108 in CYP2C9 are important determinants of the catalytic function. Biochem. Biophys. Res. Commun. 270, 983-987 (2000).
12. de Groot, M. J., Alex, A. A. & Jones, B. C. Development of a combined protein and pharmacophore nodel for cytochrome P450 2C9. J. Med. Chem. 45, 1983-1993 (2002).
13. Mancy, A., Broto, P., Dijols, S., Dansette, P. M. & Mansuy, D. The substrate binding site of human liver cytochrome P450 2C9: an approach using designed tienilic acid derivatives and molecular modeling. Biochemistry 34, 10365-10375 (1995).
14. Jones, B. C. et al. Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase). Drug Metab. Dispos. 24, 260-266 (1996).
15. Lewis, D. F. On the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics: towards the prediction of human p450 substrate specificity and metabolism. Biochem. Pharmacol. 60, 293-306 (2000).
16. Takahashi, H. & Echizen, H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin. Pharmacokinet. 40, 587-603 (2001).
17. Kaminsky, L. S. & Zhang, Z. Y. Human P450 metabolism of warfarin. Pharmacol. Ther. 73, 67-74 (1997).
18. Haining, R. L. et al. Enzymatic determinants of the substrate specificity of CYP2C9: role of B′-C loop residues in providing the pi-stacking anchor site for warfarin binding. Biochemistry 38, 3285-3292 (1999).
19. Modi, S., Sutcliffe, M. J., Primrose, W. U., Lian, L. Y. & Roberts, G. C. The catalytic mechanism of cytochrome P450 BM3 involves a 6 Å movement of the bound substrate on reduction. Nature Struct. Biol. 3, 414-417 (1996).
20. Modi, S. et al. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as a substrate of cytochrome P450 2D6: allosteric effects of NADPH-cytochrome P450 reductase. Biochemistry 36, 4461-4470 (1997).
21. Nave, C. Radiation damage in protein crystallography. Radiat. Phys. Chem. 45, 483-490 (1995).
22. Hlavica, P. & Lewis, D. F. Allosteric phenomena in cytochrome P450-catalyzed monooxygenations. European Journal of Biochemistry 268, 4817-4832 (2001).
23. Tang, W. & Stearns, R. A. Heterotropic cooperativity of cytochrome P450 3A4 and potential drug-drug interactions. Curr. Drug Metab. 2, 185-198 (2001).
24. Hutzler, J. M., Hauer, M. J. & Tracy, T. S. Dapsone activation of CYP2C9-mediated metabolism: evidence for activation of multiple substrates and a two-site model. Drug Metab. Dispos. 29, 1029-1034 (2001).
25. Hutzler, J. M., Wienkers, L. C., Wahhlstrom, J. L., Carlson, T. J. & Tracy, T. S. Activation of cytochrome P450 2C9-mediated metabolism: mechanistic evidence in support of kinetic observations. Arch. Biochem. Biophys. 410, 16-24 (2003).
26. Stresser, D. M., Ackermann, J. M., Miller, V. P. & Crespi, C. L. Fluorometric cytochromes P450 2C8, 2C9 and 2C19 inhibition assays (http://www.gentest.com/products/pdf/post_015.pdf).
27. Hemeryck, A., De Vriendt, C. & Belpaire, F. M. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes. Eur. J. Clin. Pharmacol. 54(12), 947-951 (1999).
28. Leslie, A. G. W. MOSFLM. Joint CCP4 and EESF-EACMB Newsletter on Protein Crystallography 26 (SERC Daresbury Laboratory, Warrington, 1992).
29. Navaza, J. AMoRe: an automated package for molecular replacement. Acta Crystallogr. A 50, 157-163 (1994).
30. Murshudov, G. N., Vagin, A. A. & Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D 50, 760-763 (1997).