1og5

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==Overview==
==Overview==
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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. 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. 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.
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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. 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. 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.
==About this Structure==
==About this Structure==
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[[Category: Single protein]]
[[Category: Single protein]]
[[Category: Unspecific monooxygenase]]
[[Category: Unspecific monooxygenase]]
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[[Category: Angove, H.C.]]
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[[Category: Angove, H C.]]
[[Category: Cosme, J.]]
[[Category: Cosme, J.]]
[[Category: Jhoti, H.]]
[[Category: Jhoti, H.]]
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[[Category: Vinkovic, D.Matak.]]
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[[Category: Vinkovic, D Matak.]]
[[Category: Ward, A.]]
[[Category: Ward, A.]]
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[[Category: Williams, P.A.]]
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[[Category: Williams, P A.]]
[[Category: HEC]]
[[Category: HEC]]
[[Category: SWF]]
[[Category: SWF]]
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[[Category: oxidoreductase]]
[[Category: oxidoreductase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb 3 09:57:42 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:17:22 2008''

Revision as of 12:17, 21 February 2008

Image:1og5.gif

1og5, resolution 2.55Å

Drag the structure with the mouse to rotate

STRUCTURE OF HUMAN CYTOCHROME P450 CYP2C9

Overview

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. 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. 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.

About this Structure

1OG5 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Unspecific monooxygenase, with EC number 1.14.14.1 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Crystal structure of human cytochrome P450 2C9 with bound warfarin., Williams PA, Cosme J, Ward A, Angove HC, Matak Vinkovic D, Jhoti H, Nature. 2003 Jul 24;424(6947):464-8. Epub 2003 Jul 13. PMID:12861225

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