Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody.
Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody.
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DOI：
10.1038/srep17216
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发表时间：
2015-11-24
影响因子：
4.6
通讯作者：
Spiegel PC
中科院分区：
文献类型：
--
作者：
Wuerth ME;Cragerud RK;Spiegel PC
凝血因子VIII是一种糖蛋白辅助因子，对凝血级联的内在途径至关重要。抑制性抗体要么自发产生，要么响应于向A型血友病患者输注功能性因子VIII，其中许多是针对因子VIII C2结构域的。免疫反应在很大程度上被解析为“经典”和“非经典”抑制性抗体，它们合作地结合在对立的脸上。本研究报道了3E6经典抑制抗体抗原结合片段复合物中C2结构域的2.61 Å分辨率结构。当结合界面与先前确定的C2结构域同时与两种抗体结合时，结合界面在很大程度上是保守的。进一步检测各种x射线晶体结构中C2结构域的B因子，发现3E6抗体结合降低了相对面上C2结构域表面环的热运动行为，从而表明抗体协同结合是一种动态效应。了解血友病A治疗后对因子VIII免疫反应的结构性质将有助于开发更好的治疗试剂。
Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conserved when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents.