Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation

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

doi:10.1126/science.abc5667

Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation

Journal Article · Wed Nov 04 23:00:00 EST 2020 · Science

DOI:https://doi.org/10.1126/science.abc5667· OSTI ID:1755274

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Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
NE-CAT, Cornell University, Argonne National Laboratory, Argonne, IL 60439, USA.

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.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1755274

Alternate ID(s):: OSTI ID: 1764245

Journal Information:: Science, Journal Name: Science Journal Issue: 6524 Vol. 371; ISSN 0036-8075

Publisher:: American Association for the Advancement of Science (AAAS)Copyright Statement

Country of Publication:: United States

Language:: English

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