GPR84是一种独特的孤儿型G蛋白偶联受体（GPCR），可以被内源性中链脂肪酸（MCFAs）激活。GPR84的信号传导主要是促炎性的，可以增强炎症反应，并且GPR84还作为一种促吞噬细胞受体，能够增强巨噬细胞的吞噬活性。在本研究中，我们显示合成激动剂6-OAU对GPR84的激活可以与CD47在癌细胞上的阻断相协同，诱导巨噬细胞对癌细胞的吞噬作用。我们还确定了GPR84-Gi信号传导复合物与6-OAU的高分辨率结构。该结构揭示了6-OAU的一个闭塞结合口袋，涉及GPR84非保守结构基序的受体激活的分子基础，以及一个不寻常的Gi偶联界面。结合计算对接和模拟研究，这个结构还揭示了GPR84对MCFAs的高选择性机制以及配体与解离的潜在路径。这些结果为理解GPR84信号传导和开发针对GPR84的新药物提供了框架。© 2023. Springer Nature Limited.

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 phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-Gi signaling complex with 6-OAU. This structure reveals an 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, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.© 2023. Springer Nature Limited.