CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
Nature. 2021 Jan;589(7843):620-626. doi: 10.1038/s41586-020-03083-w. Epub 2021 Jan 6.
Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available. Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97), a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-G complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W, which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the G protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the G protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.
黏附 G 蛋白偶联受体（GPCRs）是 GPCRs 的主要家族之一，但对其配体调节或结构的了解有限。在这里，我们报告糖皮质激素应激激素激活黏附 G 蛋白偶联受体 G3（ADGRG3；也称为 GPR97），这是一种典型的黏附 GPCR。与抗炎药物倍氯米松或甾体激素皮质醇结合的 GPR97-G 复合物的冷冻电子显微镜结构表明，糖皮质激素结合到跨膜域内的一个口袋中。糖皮质激素的甾体核心与“Toggle 开关”残基 W 紧贴，该残基可感应配体的结合并诱导受体的激活。活性 GPR97 使用四元核心和 HLY 基序来固定七次跨膜束并介导 G 蛋白偶联。GPR97 的细胞质侧有一个开放的腔，三个细胞内环都与 G 蛋白相互作用，这有助于 GPR97 的高基础活性。在 G 蛋白胞质尾部的棕榈酰化被发现对于与 GPR97 的有效结合是必不可少的，但在其他已解决的 GPCR 复合物结构中未观察到。我们的工作为配体结合到黏附 GPCR 的七次跨膜结构域以及随后的 G 蛋白偶联提供了结构基础。
