Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Nature. 2018 Mar 1;555(7694):121-125. doi: 10.1038/nature25773. Epub 2018 Feb 21.
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 Gα 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 Gα protein. Our structure provides insights into the molecular basis of biased agonism.
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。内源性和拟肽 GLP-1 表现出偏激动作用——功能选择性的差异——这可能提供更好的治疗效果。在这里，我们描述了人 GLP-1 受体与 G 蛋白偏倚肽 exendin-P5 和 Gα 异三聚体复合物的结构，其整体分辨率为 3.3 Å。在细胞外表面，我们的 exendin-P5 结合结构与以前的 GLP-1 结合 GLP-1 受体结构之间，细胞外环 3 和近端跨膜片段的组织不同。在细胞内表面，结构之间 Gαs-α5 螺旋结合的角度存在 6 度差异，这种差异在 G 蛋白异三聚体中传播。此外，结构在 G 蛋白构象重排的速率和程度上存在差异。我们的结构为偏激动作用的分子基础提供了见解。
