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 pollutants1. 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 use2. 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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We thank R. Mallender, L. Vuillard, S. Rich and S. Kirton for assistance with protein production, crystallization, characterization, analysis and modelling, and R. Carr, D. Cross, C. Murray and G. Williams for valuable discussions. We acknowledge the European Synchrotron Radiation Facility for provision of synchrotron radiation facilities and would like to thank the industrial user support group for assistance. The authors are grateful to F. W. Dahlquist for provision of the pCWOri + expression vector.
The authors declare that they have no competing financial interests.
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Williams, P., Cosme, J., Ward, A. et al. Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 424, 464–468 (2003). https://doi.org/10.1038/nature01862
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