Warfarin traps human Vitamin K epoxide reductase in an intermediate state during electron transfer

Guomin Shen, Weidong Cui, Hao Zhang, Fengbo Zhou, Wei Huang, Qian Liu, Yihu Yang, Shuang Li, Gregory R. Bowman, J. Evan Sadler, Michael L. Gross, Weikai Li

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Although warfarin is the most widely used anticoagulant worldwide, the mechanism by which warfarin inhibits its target, human Vitamin K epoxide reductase (hVKOR), remains unclear. Here we show that warfarin blocks a dynamic electron-transfer process in hVKOR. A major fraction of cellular hVKOR is in an intermediate redox state containing a Cys51-Cys132 disulfide, a characteristic accommodated by a four-transmembrane-helix structure of hVKOR. Warfarin selectively inhibits this major cellular form of hVKOR, whereas disruption of the Cys51-Cys132 disulfide impairs warfarin binding and causes warfarin resistance. Relying on binding interactions identified by cysteine alkylation footprinting and mass spectrometry coupled with mutagenesis analysis, we conducted structure simulations, which revealed a closed warfarin-binding pocket stabilized by the Cys51-Cys132 linkage. Understanding the selective warfarin inhibition of a specific redox state of hVKOR should enable the rational design of drugs that exploit the redox chemistry and associated conformational changes in hVKOR.

Original languageEnglish
Pages (from-to)69-76
Number of pages8
JournalNature Structural and Molecular Biology
Issue number1
StatePublished - Jan 5 2017


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