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

Content Provider	Europe PMC
Author	Holze, Janine Bermudez, Marcel Pfeil, Eva Marie Kauk, Michael Bödefeld, Theresa Irmen, Matthias Matera, Carlo Dallanoce, Clelia De Amici, Marco Holzgrabe, Ulrike König, Gabriele Maria Tränkle, Christian Wolber, Gerhard Schrage, Ramona Mohr, Klaus Hoffmann, Carsten Kostenis, Evi Bock, Andreas
Copyright Year	2020
Description	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.
Abstract	Allostericcoupling describes a reciprocal process whereby G-protein-coupledreceptors (GPCRs) relay ligand-induced conformational changes fromthe extracellular binding pocket to the intracellular signaling surface.Therefore, GPCR activation is sensitive to both the type of extracellularligand and intracellular signaling protein. We hypothesized that ligand-specificallosteric coupling may result in preferential (i.e., biased) engagementof downstream effectors. However, the structural basis underlyingligand-dependent control of this essential allosteric mechanism ispoorly understood. Here, we show that two sets of extended muscarinicacetylcholine receptor M1 agonists, which only differ inlinker length, progressively constrain receptor signaling. We demonstratethat stepwise shortening of their chemical linker gradually hampersbinding pocket closure, resulting in divergent coupling to distinctG-protein families. Our data provide an experimental strategy forthe design of ligands with selective G-protein recognition and reveala potentially general mechanism of ligand-specific allosteric coupling.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7551708&blobtype=pdf
Volume Number	3
DOI	10.1021/acsptsci.0c00069
PubMed Central reference number	PMC7551708
Issue Number	5
PubMed reference number	33073186
Journal	ACS Pharmacology & Translational Science [ACS Pharmacol Transl Sci]
e-ISSN	25759108
Language	English
Publisher	American Chemical Society
Publisher Date	2020-09-02
Access Restriction	Open
Subject Keyword	G-protein-coupled receptors allosteric coupling bitopic ligands muscarinic receptors biased signaling G-protein selectivity
Content Type	Text
Resource Type	Article
Subject	Pharmacology (medical) Pharmacology