Crystal structure of an anticoagulant protein in complex with the Gla domain of factor X

The γ-carboxyglutamic acid (Gla) domain of blood coagulation factors is responsible for Ca(2+)-dependent phospholipid membrane binding. Factor X-binding protein (X-bp), an anticoagulant protein from snake venom, specifically binds to the Gla domain of factor X. The crystal structure of X-bp in complex with the Gla domain peptide of factor X at 2.3-Å resolution showed that the anticoagulation is based on the fact that two patches of the Gla domain essential for membrane binding are buried in the complex formation. The Gla domain thus is expected to be a new target of anticoagulant drugs, and X-bp provides a basis for designing them. This structure also provides a membrane-bound model of factor X.

血液凝血因子的γ-羧基谷氨酸（γ-carboxyglutamic acid, Gla）结构域，负责介导钙离子依赖的磷脂膜结合过程。因子X结合蛋白（X-bp）是一种源自蛇毒的抗凝蛋白，可特异性结合凝血因子X的Gla结构域。本研究解析了X-bp与凝血因子X的Gla结构域肽段形成复合物的晶体结构，分辨率达2.3埃（Å），结果显示其抗凝作用的分子机制为：Gla结构域中两处对膜结合功能至关重要的区域，在复合物形成过程中被完全包埋。由此，Gla结构域有望成为抗凝药物的全新靶点，而X-bp则为这类抗凝药物的研发设计提供了结构学基础。该复合物结构同时也为凝血因子X的膜结合状态模型构建提供了参考依据。