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.

Glucagon-like peptide-1 receptor (GLP-1R) plays an important role in glucose homeostasis and treatment of type 2 diabetes. Here authors report the peptide-free crystal structure of human GLP-1R in an inactive state which reveals a unique closed conformation of the extracellular domain.

Details

Title
Full-length human GLP-1 receptor structure without orthosteric ligands
Author
Wu, Fan 1   VIAFID ORCID Logo  ; Yang, Linlin 2 ; Kaini, Hang 1 ; Laursen Mette 3   VIAFID ORCID Logo  ; Wu Lijie 4 ; Han, Gye Won 5 ; Ren Qiansheng 6 ; Roed, Nikolaj Kulahin 3 ; Lin Guangyao 7 ; Hanson, Michael A 8 ; Jiang Hualiang 9 ; Ming-Wei, Wang 10   VIAFID ORCID Logo  ; Reedtz-Runge Steffen 3   VIAFID ORCID Logo  ; Song Gaojie 11   VIAFID ORCID Logo  ; Stevens, Raymond C 12 

1  ShanghaiTech University, iHuman Institute, Shanghai, China (GRID:grid.440637.2); ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
2  Zhengzhou University, Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou, China (GRID:grid.207374.5) (ISNI:0000 0001 2189 3846) 
3  Novo Nordisk A/S, Novo Nordisk Park, Copenhagen, Denmark (GRID:grid.425956.9) 
4  ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) 
5  University of Southern California, Departments of Biological Sciences and Chemistry, Bridge Institute, USC Michelson Center for Convergent Bioscience, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
6  Novo Nordisk Research Center, Beijing, China (GRID:grid.42505.36) 
7  ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
8  GPCR Consortium, San Marcos, USA (GRID:grid.410726.6) 
9  Shanghai Institute of Materia Medica, Chinese Academy of Sciences, CAS Key Laboratory of Receptor Research, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396); Shanghai Institute of Materia Medica, Chinese Academy of Sciences, State Key Laboratory of Drug Research, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396); Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Drug Discovery and Design Center, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396) 
10  ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2); Shanghai Institute of Materia Medica, Chinese Academy of Sciences, CAS Key Laboratory of Receptor Research, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396); Shanghai Institute of Materia Medica, Chinese Academy of Sciences, The National Center for Drug Screening, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396); Fudan University, School of Pharmacy, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
11  East China Normal University, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, Shanghai, China (GRID:grid.22069.3f) (ISNI:0000 0004 0369 6365) 
12  ShanghaiTech University, iHuman Institute, Shanghai, China (GRID:grid.440637.2); ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2); University of Southern California, Departments of Biological Sciences and Chemistry, Bridge Institute, USC Michelson Center for Convergent Bioscience, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-14934-5
ProQuest document ID
2375480322
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.