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| 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 |
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