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Ligand-specific allosteric coupling controls G-protein-coupled receptor signaling

Item Type:Article
Title:Ligand-specific allosteric coupling controls G-protein-coupled receptor signaling
Creators Name:Holze, J. and Bermudez, M. and Pfeil, E.M. and Kauk, M. and Bödefeld, T. and Irmen, M. and Matera, C. and Dallanoce, C. and De Amici, M. and Holzgrabe, U. and König, G.M. and Tränkle, C. and Wolber, G. and Schrage, R. and Mohr, K. and Hoffmann, C. and Kostenis, E. and Bock, A.
Abstract:Allosteric coupling describes a reciprocal process whereby G-protein-coupled receptors (GPCRs) relay ligand-induced conformational changes from the extracellular binding pocket to the intracellular signaling surface. Therefore, GPCR activation is sensitive to both the type of extracellular ligand and intracellular signaling protein. We hypothesized that ligand-specific allosteric coupling may result in preferential (i.e., biased) engagement of downstream effectors. However, the structural basis underlying ligand-dependent control of this essential allosteric mechanism is poorly understood. Here, we show that two sets of extended muscarinic acetylcholine receptor M(1) agonists, which only differ in linker length, progressively constrain receptor signaling. We demonstrate that stepwise shortening of their chemical linker gradually hampers binding pocket closure, resulting in divergent coupling to distinct G-protein families. Our data provide an experimental strategy for the design of ligands with selective G-protein recognition and reveal a potentially general mechanism of ligand-specific allosteric coupling.
Keywords:G-Protein-Coupled Receptors, Allosteric Coupling, Bitopic Ligands, Muscarinic Receptors, Biased Signaling, G-Protein Selectivity
Source:ACS Pharmacology & Translational Science
Publisher:American Chemical Society
Page Range:859-867
Date:9 October 2020
Additional Information:Copyright © 2020 American Chemical Society
Official Publication:https://doi.org/10.1021/acsptsci.0c00069
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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