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

Autor: Holze J; Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn 53121, Germany., Bermudez M; Institute of Pharmacy, Freie Universität Berlin, Berlin 14195, Germany., Pfeil EM; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn 53121, Germany., Kauk M; Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, University Hospital Jena, Friedrich Schiller University Jena, Jena 07745, Germany., Bödefeld T; Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn 53121, Germany., Irmen M; Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn 53121, Germany., Matera C; Department of Pharmaceutical Sciences, University of Milan, Milan 20133, Italy., Dallanoce C; Department of Pharmaceutical Sciences, University of Milan, Milan 20133, Italy., De Amici M; Department of Pharmaceutical Sciences, University of Milan, Milan 20133, Italy., Holzgrabe U; Department of Pharmaceutical and Medical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg D-97074, Germany., König GM; Institute for Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany., Tränkle C; Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn 53121, Germany., Wolber G; Institute of Pharmacy, Freie Universität Berlin, Berlin 14195, Germany., Schrage R; Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn 53121, Germany., Mohr K; Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn 53121, Germany., Hoffmann C; Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, University Hospital Jena, Friedrich Schiller University Jena, Jena 07745, Germany., Kostenis E; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn 53121, Germany., Bock A; Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn 53121, Germany.; Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany.
Jazyk: angličtina
Zdroj: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2020 Sep 02; Vol. 3 (5), pp. 859-867. Date of Electronic Publication: 2020 Sep 02 (Print Publication: 2020).
DOI: 10.1021/acsptsci.0c00069
Abstrakt: 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.
Competing Interests: The authors declare no competing financial interest.
Databáze: MEDLINE
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