Ligand-specific restriction of extracellular conformational dynamics constrains signaling of the M(2) muscarinic receptor

Tools

Item Type:	Article
Title:	Ligand-specific restriction of extracellular conformational dynamics constrains signaling of the M(2) muscarinic receptor
Creators Name:	Bermudez, M., Bock, A., Krebs, F., Holzgrabe, U., Mohr, K., Lohse, M.J. and Wolber, G.
Abstract:	G protein-coupled receptors transmit extracellular signals across cell membranes via different G protein classes and {beta}-arrestins. Some pathways may be therapeutically beneficial, whereas others may be detrimental under certain pathophysiological conditions. For many GPCRs, biased agonists are available, which preferentially signal through one pathway or a subset of pathways, and harnessing biased agonism could be a potential novel therapeutic strategy. However, the incomplete mechanistic understanding of biased agonism hampers rational design of biased ligands. Using the muscarinic M(2) receptor as a model system, we have analyzed the relationship between ligand-dependent conformational changes as revealed in all-atom MD simulations and the activation of specific G proteins. We find that the extent of closure of the extracellular, allosteric binding site interferes with the activation of certain G proteins. Our data allow the rational design of Gi-biased agonists at the M(2) receptor and delineate a simple principle which may be translated to other GPRCs.
Keywords:	Allosteric Regulation, Binding Sites, Crystallography, X-Ray, Drug Design, Ligands, Molecular Dynamics Simulation, Protein Conformation, Receptor, Muscarinic M2, Signal Transduction
Source:	ACS Chemical Biology
ISSN:	1554-8929
Publisher:	American Chemical Society
Volume:	12
Number:	7
Page Range:	1743-1748
Date:	21 July 2017
Official Publication:	https://doi.org/10.1021/acschembio.7b00275
PubMed:	View item in PubMed

Repository Staff Only: item control page