小柯机器人

美国南加州大学Cornelius Gati、印度理工学院Arun K. Shukla和Ramanuj Banerjee团队合作的一项最新研究揭示了补体受体与anaphylatoxins结合、激活和信号传导偏好性的分子基础。相关论文发表在2023年10月17日出版的《细胞》杂志上。

研究人员展示了由天然和合成激动剂激活C3aR和C5aR1的九种冷冻电镜结构，揭示了补体anaphylatoxins不同结合口袋的拓扑结构，为受体激活和信号转换提供了重要见解。研究人员还揭示了蛋白水解末端精氨酸抑制C5a炎症反应发生的结构基础，以及确定该情况下C3aR多肽激动剂诱发G蛋白信号传导具有偏好性。

总之，该研究阐明了补体anaphylatoxin受体的内部结构，有助于以结构为导向的药物发现，从而在一系列疾病中靶向这些受体。

据了解，补体系统是人先天性免疫反应的重要组成部分，而这一级联的最终产物- anaphylatoxins C3a和C5a-主要通过两个GPCR（C3aR和C5aR1）发挥其生理和病理功能。然而，这些受体的配体识别、活化和信号传导偏好性的分子机制仍不清楚。

附：英文原文

Title: Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors

Author: Manish K. Yadav, Jagannath Maharana, Ravi Yadav, Shirsha Saha, Parishmita Sarma, Chahat Soni, Vinay Singh, Sayantan Saha, Manisankar Ganguly, Xaria X. Li, Samanwita Mohapatra, Sudha Mishra, Htet A. Khant, Mohamed Chami, Trent M. Woodruff, Ramanuj Banerjee, Arun K. Shukla, Cornelius Gati

Issue&Volume: 2023-10-17

Abstract: The complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological responses primarily via two GPCRs, C3aR and C5aR1. However, the molecular mechanism of ligand recognition, activation, and signaling bias of these receptors remains mostly elusive. Here, we present nine cryo-EM structures of C3aR and C5aR1 activated by their natural and synthetic agonists, which reveal distinct binding pocket topologies of complement anaphylatoxins and provide key insights into receptor activation and transducer coupling. We also uncover the structural basis of a naturally occurring mechanism to dampen the inflammatory response of C5a via proteolytic cleavage of the terminal arginine and the G-protein signaling bias elicited by a peptide agonist of C3aR identified here. In summary, our study elucidates the innerworkings of the complement anaphylatoxin receptors and should facilitate structure-guided drug discovery to target these receptors in a spectrum of disorders.

DOI: 10.1016/j.cell.2023.09.020

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01074-7