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Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation.

ABSTRACT: Vitamin K antagonists are widely used anticoagulants that target vitamin K epoxide reductases (VKOR), a family of integral membrane enzymes. To elucidate their catalytic cycle and inhibitory mechanism, we report 11 x-ray crystal structures of human VKOR and pufferfish VKOR-like, with substrates and antagonists in different redox states. Substrates entering the active site in a partially oxidized state form cysteine adducts that induce an open-to-closed conformational change, triggering reduction. Binding and catalysis are facilitated by hydrogen-bonding interactions in a hydrophobic pocket. The antagonists bind specifically to the same hydrogen-bonding residues and induce a similar closed conformation. Thus, vitamin K antagonists act through mimicking the key interactions and conformational changes required for the VKOR catalytic cycle.

SUBMITTER: Liu S

PROVIDER: S-EPMC7946407 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation.

Liu Shixuan S Li Shuang S Shen Guomin G Sukumar Narayanasami N Krezel Andrzej M AM Li Weikai W

Science (New York, N.Y.) 20201105 6524

Vitamin K antagonists are widely used anticoagulants that target vitamin K epoxide reductases (VKOR), a family of integral membrane enzymes. To elucidate their catalytic cycle and inhibitory mechanism, we report 11 x-ray crystal structures of human VKOR and pufferfish VKOR-like, with substrates and antagonists in different redox states. Substrates entering the active site in a partially oxidized state form cysteine adducts that induce an open-to-closed conformational change, triggering reduction ...[more]

PMID: 33154105

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