Abstract
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.
Highlights
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
extracellular loop 1 (ECL1) and ECL3, which were disordered in the previous transmembrane domain (TMD) structure, are ordered and form a α-helical conformation reminiscent of the peptide-bound GLP-1R structures
The antibody Fab7F38 appears to function by providing enhanced soluble surface area for crystal lattice packing, and Fab7F38-bound GLP-1R can assume an active conformation as shown by electron microscopy (EM) studies, suggesting that Fab7F38 does not interfere with the conformational flexibility of the extracellular domain (ECD) during crystallization
Summary
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. Class B G protein-coupled receptors (GPCRs), whose endogenous ligands are peptide hormones, are key mediators of normal human physiology and serve as valuable drug targets for many diseases including diabetes, metabolic syndrome, osteoporosis, migraine, depression, and anxiety[1]. They include an N-terminal 120–160 residue extracellular domain (ECD) and a C-terminal transmembrane domain (TMD), both of which are important for peptide hormone binding and activation[2]. The closed conformation of the peptide-free GLP-1R compared to GCGR is quite divergent in the extracellular region and may be a consequence of sequence diversity, which is important for understanding the signalling pathway for different receptors within the class B family
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