Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein
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Open Access
- 24 May 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 546 (7657), 248-253
- https://doi.org/10.1038/nature22394
Abstract
Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1R–Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5-helix of the Ras-like domain of Gs. These results provide a structural framework for understanding class B GPCR activation through hormone binding.Keywords
This publication has 56 references indexed in Scilit:
- RELION: Implementation of a Bayesian approach to cryo-EM structure determinationJournal of Structural Biology, 2012
- Second Extracellular Loop of Human Glucagon-like Peptide-1 Receptor (GLP-1R) Has a Critical Role in GLP-1 Peptide Binding and Receptor ActivationJournal of Biological Chemistry, 2012
- Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor functionBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2011
- Structural flexibility of the Gαs α-helical domain in the β 2 -adrenoceptor Gs complexProceedings of the National Academy of Sciences of the United States of America, 2011
- Crystal structure of the β2 adrenergic receptor–Gs protein complexNature, 2011
- Crystal Structure of Glucagon-like Peptide-1 in Complex with the Extracellular Domain of the Glucagon-like Peptide-1 ReceptorJournal of Biological Chemistry, 2010
- Agonist‐dependent consequences of proline to alanine substitution in the transmembrane helices of the calcitonin receptorBritish Journal of Pharmacology, 2007
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Biological Crystallography, 2004
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- The ribosome at improved resolution: New techniques for merging and orientation refinement in 3D cryo-electron microscopy of biological particlesUltramicroscopy, 1994