Crystal structure of human cytochrome P4502C9 with bound warfarin

被引:713
作者
Williams, PA [1 ]
Cosme, J [1 ]
Ward, A [1 ]
Angova, HC [1 ]
Vinkovic, DM [1 ]
Jhoti, H [1 ]
机构
[1] Astex Technol, Cambridge CB4 0QA, England
关键词
D O I
10.1038/nature01862
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cytochrome P450 proteins (CYP450s) are membrane-associated haem proteins that metabolize physiologically important compounds in many species of microorganisms, plants and animals. Mammalian CYP450s recognize and metabolize diverse xenobiotics such as drug molecules, environmental compounds and pollutants(1). Human CYP450 proteins CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 are the major drug-metabolizing isoforms, and contribute to the oxidative metabolism of more than 90% of the drugs in current clinical use(2). Polymorphic variants have also been reported for some CYP450 isoforms, which has implications for the efficacy of drugs in individuals, and for the co-administration of drugs. The molecular basis of drug recognition by human CYP450s, however, has remained elusive. Here we describe the crystal structure of a human CYP450, CYP2C9, both unliganded and in complex with the anti-coagulant drug warfarin. The structure defines unanticipated interactions between CYP2C9 and warfarin, and reveals a new binding pocket. The binding mode of warfarin suggests that CYP2C9 may undergo an allosteric mechanism during its function. The newly discovered binding pocket also suggests that CYP2C9 may simultaneously accommodate multiple ligands during its biological function, and provides a possible molecular basis for understanding complex drug-drug interactions.
引用
收藏
页码:464 / 468
页数:5
相关论文
共 29 条
  • [1] Cytochromes P450 and metabolism of xenobiotics
    Anzenbacher, P
    Anzenbacherová, E
    [J]. CELLULAR AND MOLECULAR LIFE SCIENCES, 2001, 58 (5-6) : 737 - 747
  • [2] Development of a combined protein and pharmacophore model for cytochrome P4502C9
    de Groot, MJ
    Alex, AA
    Jones, BC
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (10) : 1983 - 1993
  • [3] Pivotal role of water in the mechanism of P450BM-3
    Haines, DC
    Tomchick, DR
    Machius, M
    Peterson, JA
    [J]. BIOCHEMISTRY, 2001, 40 (45) : 13456 - 13465
  • [4] Enzymatic determinants of the substrate specificity of CYP2C9:: Role of B′-C loop residues in providing the π-stacking anchor site for warfarin binding
    Haining, RL
    Jones, JP
    Henne, KR
    Fisher, MB
    Koop, DR
    Trager, WF
    Rettie, AE
    [J]. BIOCHEMISTRY, 1999, 38 (11) : 3285 - 3292
  • [5] Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes
    Hemeryck, A
    De Vriendt, C
    Belpaire, FM
    [J]. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1999, 54 (12) : 947 - 951
  • [6] Allosteric phenomena in cytochrome P450-catalyzed monooxygenations
    Hlavica, P
    Lewis, DFV
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (18): : 4817 - 4832
  • [7] ADMET - turning chemicals into drugs
    Hodgson, J
    [J]. NATURE BIOTECHNOLOGY, 2001, 19 (08) : 722 - 726
  • [8] Hutzler JM, 2001, DRUG METAB DISPOS, V29, P1029
  • [9] Hutzler JM, 2003, ARCH BIOCHEM BIOPHYS, V410, P16
  • [10] Identification of residues 99, 220, and 221 of human cytochrome P450 2C19 as key determinants of omeprazole hydroxylase activity
    Ibeanu, GC
    Ghanayem, BI
    Linko, P
    Li, LP
    Pedersen, LG
    Goldstein, JA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) : 12496 - 12501