加拉地单抗抑制 βFXIIa 的结构基础

IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

摘要

活化的 FXII(FXIIa)是血浆接触系统的主要启动器,可激活促凝血和促炎症途径。它的活性在遗传性血管性水肿(HAE)的病理生理学中非常重要。在这里,我们描述了 FXIIa(βFXIIa)的β链与加拉地单抗的 Fab 片段复合物的高分辨率冷冻电子显微镜(cryo-EM)结构。Garadacimab 通过一个异常长的 CDR-H3 与 βFXIIa 结合,该 CDR-H3 以一种非规范的方式插入 S1 袋。这种结构机制可能是抑制 HAE 中活化的 FXIIa 蛋白溶解活性的主要原因。Garadacimab Fab-βFXIIa 结构还揭示了 Garadacimab 与活化 FXIIa 高亲和力结合的关键决定因素。与其他真正的 FXIIa 抑制剂(如联苯胺和 C1-INH)进行的结构分析表明,garadacimab 对 βFXIIa 的抑制机制惊人地相似。总之,garadacimab Fab-βFXIIa 结构为了解其作用机制提供了重要信息,并勾画出了主要和辅助副基团/表位。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Structural basis for the inhibition of βFXIIa by garadacimab

Structural basis for the inhibition of βFXIIa by garadacimab

Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of βFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.

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来源期刊
Structure
Structure 生物-生化与分子生物学
CiteScore
8.90
自引率
1.80%
发文量
155
审稿时长
3-8 weeks
期刊介绍: Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.
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