The raw data for S6A Fig.

Chemokine-like receptor 1 (CMKLR1), also known as chemerin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein–coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, including macrophages and neutrophils. The signaling pathways of CMKLR1 can lead to both pro- and anti-inflammatory effects depending on the ligands and physiological contexts. To understand the molecular mechanisms of CMKLR1 signaling, we determined a high-resolution cryo-electron microscopy (cryo-EM) structure of the CMKLR1-Gi signaling complex with chemerin9, a nanopeptide agonist derived from chemerin, which induced complex phenotypic changes of macrophages in our assays. The cryo-EM structure, together with molecular dynamics simulations and mutagenesis studies, revealed the molecular basis of CMKLR1 signaling by elucidating the interactions at the ligand-binding pocket and the agonist-induced conformational changes. Our results are expected to facilitate the development of small molecule CMKLR1 agonists that mimic the action of chemerin9 to promote the resolution of inflammation.

趋化因子样受体1（Chemokine-like receptor 1, CMKLR1），又称趋化素受体23（chemerin receptor 23, ChemR23）或趋化素受体1，是一类可识别脂肪因子趋化素（chemerin）的趋化性G蛋白偶联受体（G protein–coupled receptor, GPCR），在巨噬细胞、中性粒细胞等先天免疫细胞中呈高表达。CMKLR1的信号通路可根据配体类型与生理环境不同，同时介导促炎与抗炎效应。为阐明CMKLR1信号转导的分子机制，我们解析了CMKLR1-Gi信号复合物与趋化素衍生的纳米肽激动剂chemerin9的高分辨率冷冻电子显微镜（cryo-electron microscopy, cryo-EM）结构；在本研究的实验体系中，chemerin9可诱导巨噬细胞产生复杂的表型变化。该冷冻电镜结构结合分子动力学模拟与诱变研究，通过揭示配体结合口袋内的相互作用模式以及激动剂诱导的构象变化，阐明了CMKLR1信号转导的分子基础。本研究结果有望助力开发模拟chemerin9功能的小分子CMKLR1激动剂，以促进炎症消退。