The Crystal Structure of the Active Domain of Anopheles Anti-platelet Protein, a Powerful Anti-coagulant, in Complex with an Antibody*
The Crystal Structure of the Active Domain of Anopheles Anti-platelet Protein, a Powerful Anti-coagulant, in Complex with an Antibody*
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DOI：
10.1074/jbc.m114.564526
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发表时间：
2014-04
期刊：
影响因子：
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通讯作者：
K. Sugiyama;M. Iyori;Asuka Sawaguchi;S. Akashi;J. Tame;Sam-Yong Park;S. Yoshida
中科院分区：
文献类型：
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作者：
K. Sugiyama;M. Iyori;Asuka Sawaguchi;S. Akashi;J. Tame;Sam-Yong Park;S. Yoshida
背景：天然存在的抗凝蛋白质为具有高度理想特性的新药物提供了模型。结果：解决了蚊子蛋白AAPP活性区的晶体结构。结论：蚊子蛋白AAPP利用一个小的转弯区域，通过结合胶原蛋白，非常有效地阻断凝血。意义：新的小分子抗凝剂可能会开发出全新的机制，并且没有当前治疗的缺点。凝血是一个非常重要的过程，必须仔细调节，以防止一方面失血和另一方面血栓形成。严重损伤和血友病可使用促凝血剂治疗，而使用抗凝剂可降低阻塞性凝血或栓塞的风险。抗凝剂是一类极其重要的药物，是最广泛使用的药物类型之一，但是仍然迫切需要新的治疗方法，因为目前的药物如华法林具有显著的缺点。《自然》提供了许多由吸血动物产生的抗凝蛋白的例子，这些例子可能为开发具有类似生理作用的新小分子提供模板。因此，我们研究了一种来自疟疾媒介蚊子的按蚊抗血小板蛋白，并报告了其与抗体复合的晶体结构。总的来说，该蛋白对蛋白水解非常敏感，但晶体结构显示了由两个螺旋和一个转角构建的稳定结构域，其对应于功能区域。针对按蚊抗血小板蛋白的抗体阻止其结合胶原蛋白。因此，我们的工作为开发新型小分子抗凝剂和抗疟疾药物开辟了新的途径。
Background: Naturally occurring anticoagulant proteins provide models for new medications with highly desirable properties. Results: The crystal structure of the active region of mosquito protein AAPP has been solved. Conclusion: The mosquito protein AAPP uses a small turn region to block coagulation extremely effectively by binding collagen. Significance: New small molecule anti-coagulants may be developed with completely new mechanisms and none of the drawbacks of current treatments. Blood clotting is a vitally important process that must be carefully regulated to prevent blood loss on one hand and thrombosis on the other. Severe injury and hemophilia may be treated with pro-coagulants, whereas risk of obstructive clotting or embolism may be reduced with anti-coagulants. Anti-coagulants are an extremely important class of drug, one of the most widely used types of medication, but there remains a pressing need for novel treatments, however, as present drugs such as warfarin have significant drawbacks. Nature provides a number of examples of anti-coagulant proteins produced by blood-sucking animals, which may provide templates for the development of new small molecules with similar physiological effects. We have, therefore, studied an Anopheles anti-platelet protein from a malaria vector mosquito and report its crystal structure in complex with an antibody. Overall the protein is extremely sensitive to proteolysis, but the crystal structure reveals a stable domain built from two helices and a turn, which corresponds to the functional region. The antibody raised against Anopheles anti-platelet protein prevents it from binding collagen. Our work, therefore, opens new avenues to the development of both novel small molecule anti-clotting agents and anti-malarials.