Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 1, Pages 69-76Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3333
Keywords
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Funding
- DOE [DE-SC0001035]
- China Scholarship Council [201206235027]
- BWF Career Award
- NIH NHLBI [R01 HL130446, U54 HL112303]
- NIH NIGMS [P41 GM103422]
- NHLBI [R01 HL121718]
- AHA [14GRNT20310017]
- ASH Scholar Award
- U.S. Department of Energy (DOE) [DE-SC0001035] Funding Source: U.S. Department of Energy (DOE)
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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.
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