Structure and dynamics of the CGRP receptor in apo and peptide-bound forms
- 8 April 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 372 (6538), 147-+
- https://doi.org/10.1126/science.abf7258
Abstract
G protein-coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only a limited understanding of the behavior of GPCRs in the apo state and the conformational changes upon agonist binding that lead to G protein recruitment and activation. We expressed and purified unmodified apo and peptide-bound calcitonin gene-related peptide (CGRP) receptors from insect cells to determine their cryo-electron microscopy (cryo-EM) structures, and we complemented these with analysis of protein conformational dynamics using hydrogen-deuterium exchange mass spectrometry and three-dimensional variance analysis of the cryo-EM data. Together with our previously published structure of the active, Gs-bound CGRP receptor complex, our work provides insight into the mechanisms of class B1 GPCR activation.Keywords
Funding Information
- Australian Research Council (IC200100052)
- Australian Research Council (DP210101504)
- National Health and Medical Research Council (1120919)
- National Health and Medical Research Council (1159006)
- National Health and Medical Research Council (1150083)
- National Health and Medical Research Council (1154434)
- Skretting Aquaculture Research Centre (IC200100052)
- Skretting Aquaculture Research Centre (DP210101504)
- National Health and Medical Research Council (1120919)
- National Health and Medical Research Council (1159006)
- National Health and Medical Research Council (1150083)
- Precursory Research for Embryonic Science and Technology (18069571)
- Australian Research Council Future Fellowship (FT160100075)
- National Health and Medical Research Council (1155302)
- Japan Science and Technology Agency (18069571)
- Victorian Endowment for Science Knowledge and Innovation
This publication has 54 references indexed in Scilit:
- Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studiesJournal of The Royal Society Interface, 2013
- Molecular basis for negative regulation of the glucagon receptorProceedings of the National Academy of Sciences of the United States of America, 2012
- Receptor-G Protein Interaction Studied by Bioluminescence Resonance Energy Transfer: Lessons from Protease-Activated Receptor 1Frontiers in Endocrinology, 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
- Features and development of CootActa Crystallographica Section D-Biological Crystallography, 2010
- Structure−Function Analysis of RAMP1 by Alanine MutagenesisBiochemistry, 2008
- HOLLOW: Generating Accurate Representations of Channel and Interior Surfaces in Molecular StructuresBMC Structural Biology, 2008
- Scalable molecular dynamics with NAMDJournal of Computational Chemistry, 2005
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- Constitutive Activity of Glucagon Receptor MutantsMolecular Endocrinology, 1997