Stabilization of warfarin-binding pocket of VKORC1 and VKORL1 by a peripheral region determines their different sensitivity to warfarin inhibition.

ABSTRACT: Essentials VKORL1 and VKORC1 have a similar overall structure and warfarin-binding pocket. A peripheral region stabilizing this pocket controls warfarin sensitivity of the VKOR paralogs. A human single nucleotide polymorphism in this region renders VKORL1 sensitive to warfarin. A group of warfarin-resistant mutations in VKORC1 acts by disrupting peripheral interactions.

Summary

Background The human genome encodes two paralogs of vitamin-K-epoxide reductase, VKORC1 and VKORL1, that support blood coagulation and other vitamin-K-dependent processes. Warfarin inhibits both enzymes, but VKORL1 is relatively resistant to warfarin. Objectives To understand the difference between VKORL1 and VKORC1, and the cause of warfarin-resistant (WR) mutations in VKORC1. Methods We performed systematic

SUBMITTER: Shen G 

PROVIDER: S-EPMC6231229 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature