5 years ago

Ligand-Specific Restriction of Extracellular Conformational Dynamics Constrains Signaling of the M2 Muscarinic Receptor

Ligand-Specific Restriction of Extracellular Conformational Dynamics Constrains Signaling of the M2 Muscarinic Receptor
Ulrike Holzgrabe, Andreas Bock, Klaus Mohr, Martin J. Lohse, Marcel Bermudez, Fabian Krebs, Gerhard Wolber
G protein-coupled receptors transmit extracellular signals across cell membranes via different G protein classes and β-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 M2 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 M2 receptor and delineate a simple principle which may be translated to other GPRCs.

Publisher URL: http://dx.doi.org/10.1021/acschembio.7b00275

DOI: 10.1021/acschembio.7b00275

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