CXC趨化因子受體2激活和信號傳導的結構基礎獲解析
作者：
小柯機器人發布時間：2020/7/3 14:00:33
上海科技大學劉志傑、華甜等研究人員合作解析了CXC趨化因子受體2激活和信號傳導的結構基礎。相關論文於2020年7月1日在線發表在《自然》雜誌上。
研究人員報導了白細胞介素8（IL8，也稱為CXCL8）激活的人類CXC趨化因子受體2（CXCR2）與Gi蛋白複合的冷凍電鏡結構，以及設計的變構拮抗劑結合的CXCR2晶體結構。這些結果揭示了CXCL8和CXCR2之間以及CXCR2–Gi蛋白相互作用的獨特的淺層結合模式。對CXCR2的非活躍狀態和活躍狀態的進一步結構分析揭示了一個獨特的激活過程以及趨化因子受體的競爭性小分子拮抗作用。
此外，這項研究為內源性蛋白質分子如何激活G蛋白偶聯受體（GPCR）提供了新見解，這將有助於開發靶向趨化因子系統的療法，從而獲得更好的藥理作用。
據介紹，趨化因子及其受體介導細胞遷移，從而影響多種基本的生物學過程和疾病狀況，例如炎症和癌症。儘管已經對趨化因子受體的結構研究和受體-趨化因子識別進行了充分研究，但對內源性趨化因子誘導的受體激活和G蛋白偶聯的了解還很少。
附：英文原文
Title: Structural basis of CXC chemokine receptor 2 activation and signalling
Author: Kaiwen Liu, Lijie Wu, Shuguang Yuan, Meng Wu, Yueming Xu, Qianqian Sun, Shu Li, Suwen Zhao, Tian Hua, Zhi-Jie Liu
Issue&Volume: 2020-07-01
Abstract: Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions, such as inflammation and cancer1. Although ample efforts have been invested into the structural investigation of the chemokine receptors and receptor–chemokine recognition2–4, less is known about endogenous chemokine-induced receptor activation and G protein coupling. Here, we report the cryo-electron microscopy structures of interleukin-8 (IL8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with Gi protein, along with a designed allosteric antagonist-bound CXCR2 crystal structure. Our results uncover a unique shallow binding mode between CXCL8 and CXCR2, as well as CXCR2–Gi protein interactions. Further structural analysis of CXCR2’s inactive and active states reveals a distinct activation process and the competitive small molecule antagonism of chemokine receptors. In addition, this study provides new insights into how a G protein-coupled receptor (GPCR) is activated by an endogenous protein molecule, which will assist the rational development of therapeutics targeting the chemokine system for better pharmacological profiles.
DOI: 10.1038/s41586-020-2492-5
Source: https://www.nature.com/articles/s41586-020-2492-5