Structures and cellular functions of vitamin K epoxide reductase (VKOR)
VKOR sustains blood coagulation and bone metabolism in mammals. VKOR is the target of warfarin, an oral anticoagulant that is widely used to treat thromboembolic diseases including stroke and myocardial Infarction. Bacterial VKOR homologs catalyze disulfide formation in secreted proteins by cooperating with a redox partner. We have determined the first crystal structure in this VKOR family, which shows a VKOR homolog in complex with its naturally fused redox partner. We have solved structures of this VKOR homolog in different electron-transfer states to show dynamic conformational changes at the membrane interface that promotes the catalysis. Using the structural insight, we have isolated the human redox partners for VKOR. We developed live-cell MS methods and conducted functional experiments to resolve the much-debated membrane topology and electron-transfer process of human VKOR. We also found that warfarin is a conformational inhibitor of the human VKOR with a critical disulfide. We showed that different warfarin responses of VKOR and VKOR-like are determined by interactions that indirectly affect warfarin binding, and identified warfarin-sensitive variants of VKOR-like. Importantly, we have recently obtained the structures of human VKOR with substrates and with vitamin K antagonists including warfarin, and structures of VKOR-like in different states (unpublished). After more than six decades of clinical experience with warfarin, our findings may finally lead to the improved strategy of warfarin dose regulation.
Left: structural transition of the catalytic cycle of VKOR. Right: transition induced by warfarin binding.
S. Liu et al., . Science 10.1126/science.abc5667 (2020).