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.
Science. 2021 Jan 1;371(6524). doi: 10.1126/science.abc5667. Epub 2020 Nov 5.
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.
维生素 K 拮抗剂是广泛使用的抗凝剂，它们靶向维生素 K 环氧化物还原酶（VKOR），这是一类整合膜酶。为了阐明它们的催化循环和抑制机制，我们报告了 11 个人类 VKOR 和河豚 VKOR 样的 X 射线晶体结构，其中包含不同氧化还原状态的底物和拮抗剂。进入活性位点的部分氧化状态的底物形成半胱氨酸加合物，诱导开-闭构象变化，触发还原。氢键相互作用在疏水性口袋中促进结合和催化。拮抗剂特异性结合到相同的氢键残基上，并诱导类似的封闭构象。因此，维生素 K 拮抗剂通过模拟 VKOR 催化循环所需的关键相互作用和构象变化起作用。
