Full-length human GLP-1 receptor structure without orthosteric ligands
Full-length human GLP-1 receptor structure without orthosteric ligands
复制标题
无正位配体的全长人 GLP-1 受体结构
DOI：
10.1038/s41467-020-14934-5
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发表时间：
2020-03-09
影响因子：
16.6
通讯作者：
Stevens, Raymond C.
中科院分区：
文献类型：
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作者：
Wu, Fan;Yang, Linlin;Stevens, Raymond C.
胰高血糖素样肽-1受体（GLP-1 R）是一种B类G蛋白偶联受体，在维持血糖稳态和治疗2型糖尿病中起重要作用。全长B类受体的结构是在与其正构激动剂肽的复合物中确定的，然而，在不存在正构配体的情况下，对它们的胞外结构域（ECD）的构象知之甚少，这限制了我们对其激活机制的理解。在此，我们报告了处于非活性状态的全长人GLP-1 R的3.2 nm分辨率、无肽晶体结构，这揭示了ECD的独特闭合构象。二硫键交联验证了闭合构象的生理相关性，而电子显微镜（EM）和分子动力学（MD）模拟表明，结合GLP-1所必需的ECD的构象动力学程度很大。我们的非活性结构代表了无肽GLP-1 R的快照，并提供了对该受体家族激活途径的见解。
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.