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

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Item Type:	Article
Title:	Ligand-specific allosteric coupling controls G-protein-coupled receptor signaling
Creators Name:	Holze, J., Bermudez, M., Pfeil, E.M., Kauk, M., Bödefeld, T., Irmen, M., Matera, C., Dallanoce, C., De Amici, M., Holzgrabe, U., König, G.M., Tränkle, C., Wolber, G., Schrage, R., Mohr, K., Hoffmann, C., 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
ISSN:	2575-9108
Publisher:	American Chemical Society
Volume:	3
Number:	5
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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