The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism—a difference in functional selectivity—that may provide improved therapeutic outcomes. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gαs heterotrimer, determined at a global resolution of 3.3 Å. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure. At the intracellular face, there was a six-degree difference in the angle of the Gαs–α5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Gαs protein. Our structure provides insights into the molecular basis of biased agonism.

中文翻译：

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偏向激动剂结合的人 GLP-1 受体-Gs 复合物的相位板冷冻电镜结构

B 类胰高血糖素样肽-1 (GLP-1) G 蛋白偶联受体是治疗 2 型糖尿病和肥胖症的主要靶点。内源性和模拟 GLP-1 肽表现出偏向激动作用——功能选择性的差异——这可能会提供更好的治疗结果。在这里，我们描述了与 G 蛋白偏向肽 exendin-P5 和 Gαs 异源三聚体复合的人类 GLP-1 受体的结构，以 3.3 Å 的全局分辨率确定。在细胞外表面，细胞外环 3 和近端跨膜段的组织在我们的 exendin-P5 结合结构和以前的 GLP-1 结合 GLP-1 受体结构之间有所不同。在细胞内表面，结构之间 Gαs-α5 螺旋接合的角度存在 6 度差异，该角度在 G 蛋白异源三聚体中传播。此外，这些结构在 Gαs 蛋白构象重组的速度和程度方面存在差异。我们的结构提供了对偏向激动的分子基础的见解。