Open AccessLigand-Specific Allosteric Coupling Controls G-Protein-Coupled Receptor Signaling
Author(s) -
Janine Holze,
Marcel Bermudez,
Eva Marie Pfeil,
Michael Kauk,
Theresa Bödefeld,
Matthias Irmen,
Carlo Matera,
Clelia Dallanoce,
Marco De Amici,
Ulrike Holzgrabe,
Gabriele M. König,
Christian Tränkle,
Gerhard Wolber,
R Schrage,
Klaus Mohr,
Carsten Hoffmann,
Evi Kostenis,
Andreas Böck
Publication year - 2020
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.0c00069
Subject(s) - allosteric regulation , g protein coupled receptor , ligand (biochemistry) , allosteric enzyme , biophysics , linker , chemistry , intracellular , receptor , signal transduction , allosteric modulator , coupling (piping) , microbiology and biotechnology , biology , biochemistry , materials science , computer science , metallurgy , operating system
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.