维生素K拮抗剂催化抗凝循环的结构基础，这一成果由华盛顿大学医学院的Weikai Li研究团队经过不懈努力而取得。相关论文于2020年11月5日发表于《科学》杂志。

为了阐明维生素K拮抗剂的催化循环和抑制机理，研究人员解析了带有不同氧化还原状态底物和拮抗剂的人维生素K环氧还原酶（VKOR）和河豚VKOR的11种X射线晶体结构。 以部分氧化状态进入活性位点的底物形成半胱氨酸加合物，该半胱氨酸加合物诱导开闭构象变化，从而诱发还原反应。

疏水口袋中的氢键相互作用促进了结合和催化反应。拮抗剂特异性结合相同的氢键残基并诱导相似的闭合构象。因此，维生素K拮抗剂通过模仿VKOR催化循环所需的关键相互作用和构象变化起作用。

据悉，维生素K拮抗剂是一种针对VKOR（一种整合膜酶家族）的广泛抗凝剂。

附：英文原文

Title: Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation

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

Issue&Volume: 2020/11/05

Abstract: Vitamin K antagonists are widely used anticoagulants targeting vitamin K epoxide reductases (VKOR), a family of integral membrane enzymes. To elucidate their catalytic cycle and inhibitory mechanism, here we report eleven 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 a cysteine adduct that induces an open-to-closed conformational change, triggering reduction. Binding and catalysis is 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.

DOI: 10.1126/science.abc5667

Source: https://science.sciencemag.org/content/early/2020/11/04/science.abc5667