iHuman Institute, ShanghaiTech University, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Nat Commun. 2020 Mar 9;11(1):1272. doi: 10.1038/s41467-020-14934-5.
Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures of full-length class B receptors were determined in complex with their orthosteric agonist peptides, however, little is known about their extracellular domain (ECD) conformations in the absence of orthosteric ligands, which has limited our understanding of their activation mechanism. Here, we report the 3.2 Å resolution, peptide-free crystal structure of the full-length human GLP-1R in an inactive state, which reveals a unique closed conformation of the ECD. Disulfide cross-linking validates the physiological relevance of the closed conformation, while electron microscopy (EM) and molecular dynamic (MD) simulations suggest a large degree of conformational dynamics of ECD that is necessary for binding GLP-1. Our inactive structure represents a snapshot of the peptide-free GLP-1R and provides insights into the activation pathway of this receptor family.
胰高血糖素样肽-1 受体（GLP-1R）是一种 B 类 G 蛋白偶联受体，在葡萄糖稳态和 2 型糖尿病治疗中发挥重要作用。全长 B 类受体的结构已与它们的内源性激动肽复合物确定，然而，在没有内源性配体的情况下，它们细胞外结构域（ECD）构象知之甚少，这限制了我们对其激活机制的理解。在这里，我们报告了全长人 GLP-1R 在非活性状态下的 3.2 Å 分辨率、无肽晶体结构，揭示了 ECD 的独特封闭构象。二硫键交联验证了封闭构象的生理相关性，而电子显微镜（EM）和分子动力学（MD）模拟表明 ECD 的构象动力学具有很大的自由度，这对于结合 GLP-1 是必要的。我们的无肽结构代表了 GLP-1R 的无肽快照，为该受体家族的激活途径提供了见解。
