The class A adenosine A1 receptor (A1R) is a G-protein-coupled receptor that preferentially couples to inhibitory Gi/o heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targeted. Here we report the 3.6 Å structure of the human A1R in complex with adenosine and heterotrimeric Gi2 protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive A1R, there is contraction at the extracellular surface in the orthosteric binding site mediated via movement of transmembrane domains 1 and 2. At the intracellular surface, the G protein engages the A1R primarily via amino acids in the C terminus of the Gαi α5-helix, concomitant with a 10.5 Å outward movement of the A1R transmembrane domain 6. Comparison with the agonist-bound β2 adrenergic receptor–Gs-protein complex reveals distinct orientations for each G-protein subtype upon engagement with its receptor. This active A1R structure provides molecular insights into receptor and G-protein selectivity.The cryo-electron microscopy structure of the human adenosine A1 receptor in complex with adenosine and heterotrimeric Gi2 protein provides molecular insights into receptor and G-protein selectivity.

中文翻译：

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腺苷结合的人腺苷 A1 受体-Gi 复合物的结构

A 类腺苷 A1 受体 (A1R) 是一种 G 蛋白偶联受体，优先与抑制性 Gi/o 异源三聚体 G 蛋白偶联，与多种疾病有关，但仍然缺乏针对性。在这里，我们报告了由 Volta 相位板冷冻电子显微镜确定的与腺苷和异源三聚体 Gi2 蛋白复合的人类 A1R 的 3.6 Å 结构。与无活性的 A1R 相比，通过跨膜结构域 1 和 2 的运动介导的正构结合位点的细胞外表面收缩。在细胞内表面，G 蛋白主要通过 Gαi α5 C 末端的氨基酸与 A1R 结合-螺旋，伴随着 A1R 跨膜结构域 6 向外移动 10.5 埃。与激动剂结合的 β2 肾上腺素能受体-Gs 蛋白复合物的比较揭示了每个 G 蛋白亚型与其受体结合后的不同方向。这种活性 A1R 结构提供了对受体和 G 蛋白选择性的分子洞察。人类腺苷 A1 受体与腺苷和异源三聚体 Gi2 蛋白复合物的冷冻电子显微镜结构提供了对受体和 G 蛋白选择性的分子洞察。