Zhang Xuan, Wang Yujing, Supekar Shreyas, Cao Xu, Zhou Jingkai, Dang Jessica, Chen Siqi, Jenkins Laura, Marsango Sara, Li Xiu, Liu Guibing, Milligan Graeme, Feng Mingye, Fan Hao, Gong Weimin, Zhang Cheng
Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Res Sq. 2023 Feb 15:rs.3.rs-2535247. doi: 10.21203/rs.3.rs-2535247/v1.
GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance the phagocytic activities of macrophages. In this study, we first showed that the activation of GPR84 by the synthetic agonist 6-OAU could synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. Then, we determined a high-resolution structure of the GPR84-Gi signaling complex with 6-OAU. This structure revealed a completely occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual Gi-coupling interface. Together with computational docking and simulations studies, our structure also suggested the mechanism for the high selectivity of GPR84 for MCFAs and the potential routes of ligand binding and dissociation. Our results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.
GPR84是一种独特的孤儿G蛋白偶联受体（GPCR），可被内源性中链脂肪酸（MCFA）激活。GPR84的信号传导在很大程度上具有促炎作用，可增强炎症反应，并且GPR84还作为促吞噬受体发挥作用，以增强巨噬细胞的吞噬活性。在本研究中，我们首先表明，合成激动剂6-OAU激活GPR84可与癌细胞上CD47的阻断协同作用，诱导巨噬细胞对癌细胞的吞噬作用。然后，我们确定了与6-OAU结合的GPR84-Gi信号复合物的高分辨率结构。该结构揭示了一个完全封闭的6-OAU结合口袋、涉及GPR84非保守结构基序的受体激活分子基础以及一个不寻常的Gi偶联界面。结合计算对接和模拟研究，我们的结构还揭示了GPR84对MCFA具有高选择性的机制以及配体结合和解离的潜在途径。我们的结果为理解GPR84信号传导和开发靶向GPR84的新药提供了一个框架。
