Full-length human GLP-1 receptor structure without orthosteric ligands

Fan Wu, Linlin Yang, Kaini Hang, Mette Laursen, Lijie Wu, Gye Won Han, Qiansheng Ren, Nikolaj Kulahin Roed, Guangyao Lin, Michael A. Hanson, Hualiang Jiang, Ming-Wei Wang, Steffen Reedtz-Runge, Gaojie Song () and Raymond C. Stevens ()
Additional contact information
Fan Wu: ShanghaiTech University
Linlin Yang: Zhengzhou University
Kaini Hang: ShanghaiTech University
Mette Laursen: Novo Nordisk A/S, Novo Nordisk Park
Lijie Wu: ShanghaiTech University
Gye Won Han: University of Southern California
Qiansheng Ren: Novo Nordisk Research Center
Nikolaj Kulahin Roed: Novo Nordisk A/S, Novo Nordisk Park
Guangyao Lin: ShanghaiTech University
Michael A. Hanson: GPCR Consortium
Hualiang Jiang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Ming-Wei Wang: ShanghaiTech University
Steffen Reedtz-Runge: Novo Nordisk A/S, Novo Nordisk Park
Gaojie Song: East China Normal University
Raymond C. Stevens: ShanghaiTech University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14934-5

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