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 M1 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.

Ligand-Specific Allosteric Coupling Controls G-Protein-Coupled Receptor Signaling / J. Holze, M. Bermudez, E.M. Pfeil, M. Kauk, T. Bödefeld, M. Irmen, C. Matera, C. Dallanoce, M. De Amici, U. Holzgrabe, G.M. König, C. Tränkle, G. Wolber, R. Schrage, K. Mohr, C. Hoffmann, E. Kostenis, A. Bock. - In: ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE. - ISSN 2575-9108. - 3:5(2020 Oct 09), pp. 859-867. [10.1021/acsptsci.0c00069]

Ligand-Specific Allosteric Coupling Controls G-Protein-Coupled Receptor Signaling

C. Matera;C. Dallanoce;M. De Amici;
2020

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 M1 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.
G-protein-coupled receptors allosteric coupling bitopic ligands muscarinic receptors biased signaling G-protein selectivity;
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
9-ott-2020
set-2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/768713
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