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

Shixuan Liu, Shuang Li, Guomin Shen, Narayanasami Sukumar, Andrzej M Krezel, Weikai Li

Science (New York, N.Y.) 2021 Jan 01

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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. Copyright © 2021, American Association for the Advancement of Science.

Citation

Shixuan Liu, Shuang Li, Guomin Shen, Narayanasami Sukumar, Andrzej M Krezel, Weikai Li. Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation. Science (New York, N.Y.). 2021 Jan 01;371(6524)