The Allosteric Vestibule of a Seven Transmembrane Helical Receptor Controls G-protein Coupling

Overview

Journal Nat Commun

Specialty Biology

Date 2012 Sep 6

PMID 22948826

Citations 52

Authors

Andreas Bock

Nicole Merten

Ramona Schrage

Clelia Dallanoce

Julia Batz

Jessica Klockner

Jens Schmitz

Carlo Matera

Katharina Simon

Anna Kebig

Lucas Peters

Anke Muller

Jasmin Schrobang-Ley

Christian Trankle

Carsten Hoffmann

Marco De Amici

Ulrike Holzgrabe

Evi Kostenis

Klaus Mohr

Affiliations

Soon will be listed here.

Abstract

Seven transmembrane helical receptors (7TMRs) modulate cell function via different types of G proteins, often in a ligand-specific manner. Class A 7TMRs harbour allosteric vestibules in the entrance of their ligand-binding cavities, which are in the focus of current drug discovery. However, their biological function remains enigmatic. Here we present a new strategy for probing and manipulating conformational transitions in the allosteric vestibule of label-free 7TMRs using the M(2) acetylcholine receptor as a paradigm. We designed dualsteric agonists as 'tailor-made' chemical probes to trigger graded receptor activation from the acetylcholine-binding site while simultaneously restricting spatial flexibility of the receptor's allosteric vestibule. Our findings reveal for the first time that a 7TMR's allosteric vestibule controls the extent of receptor movement to govern a hierarchical order of G-protein coupling. This is a new concept assigning a biological role to the allosteric vestibule for controlling fidelity of 7TMR signalling.

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