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

Nature Communications
Fan WuRaymond C Stevens

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.

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Citations

Jun 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Giulio MattediFrancesco Luigi Gervasio
Aug 9, 2020·The Journal of Biological Chemistry·Alexander VizurragaGregory G Tall
Jan 21, 2021·The Journal of Membrane Biology·Khuraijam Dhanachandra Singh, Sadashiva S Karnik
Nov 13, 2020·Proceedings of the National Academy of Sciences of the United States of America·Takahiro KawaiKyle W Sloop
Jan 9, 2021·Signal Transduction and Targeted Therapy·Dehua YangMing-Wei Wang
Oct 8, 2020·Molecular Cell·Xin ZhangDenise Wootten
Apr 24, 2020·Bioorganic Chemistry·Xinxian DengFaqin Jiang
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Aug 26, 2021·EJNMMI Radiopharmacy and Chemistry·Veronika Barbara Felber, Hans-Jürgen Wester
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Sep 1, 2021·Journal of Chemical Information and Modeling·Mengrong LiJingjing Guo
Sep 14, 2021·Frontiers in Molecular Biosciences·Giuseppe DeganuttiChristopher A Reynolds

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Methods Mentioned

BETA
electron microscopy
crosslinking
transfection
size-exclusion chromatography

Software Mentioned

PyMOL
cryoSPARC
MODELLER
CTFFIND4
CHARMM36
GROMACS
PDBePISA
Genewiz
KAMO
POVME

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