Orthosteric and allosteric action of the C5a receptor antagonists
Orthosteric and allosteric action of the C5a receptor antagonists
复制标题
C5a 受体拮抗剂的正构和变构作用
DOI：
10.1038/s41594-018-0067-z
复制
发表时间：
2018-06-01
影响因子：
16.8
通讯作者：
Zhang, Cheng
中科院分区：
文献类型：
--
作者：
Liu, Heng;Kim, Hee Ryung;Zhang, Cheng
C5a受体（C5aR）是一种G蛋白偶联受体（GPCR），可诱导对过敏毒素C5a的强烈炎症反应。靶向C5aR已成为一种新的抗炎治疗方法。然而，开发有效的C5aR拮抗剂作为药物已被证明是困难的。在这里，我们报告了两个晶体结构的人C5aR在三元复合物与肽拮抗剂PMX53和非肽拮抗剂，无论是avacopan或NDT9513727。这些结构与其他生物物理学、计算对接和基于细胞的信号传导数据一起揭示了PMX53的正构作用及其稳定C5aR结构的作用，以及具有不同结合位姿的化学多样性非肽C5aR拮抗剂的变构作用。结构比较分析表明在其他GPCR中存在类似的变构位点。我们还讨论了C5aR在激活中的关键结构特征，包括螺旋8的新构象。基于我们的研究结果，我们提出了开发C5aR靶向药物的新策略。
The C5a receptor (C5aR) is a G-protein-coupled receptor (GPCR) that can induce strong inflammatory response to the anaphylatoxin C5a. Targeting C5aR has emerged as a novel anti-inflammatory therapeutic method. However, developing potent C5aR antagonists as drugs has proven difficult. Here, we report two crystal structures of human C5aR in ternary complexes with the peptide antagonist PMX53 and a non-peptide antagonist, either avacopan or NDT9513727. The structures, together with other biophysical, computational docking and cell-based signaling data, reveal the orthosteric action of PMX53 and its effect of stabilizing the C5aR structure, as well as the allosteric action of chemically diverse non-peptide C5aR antagonists with different binding poses. Structural comparison analysis suggests the presence of similar allosteric sites in other GPCRs. We also discuss critical structural features of C5aR in activation, including a novel conformation of helix 8. On the basis of our results, we suggest novel strategies for developing C5aR-targeting drugs.