Seven transmembrane helical receptors (7TmRs) modulate cell function via different typesof G proteins, often in a ligand-specific manner. Class A 7TmRs harbour allosteric vestibulesin 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 forprobing and manipulating conformational transitions in the allosteric vestibule of label-free7TmRs using the m2acetylcholine receptor as a paradigm. We designed dualsteric agonistsas ‘tailor-made’ chemical probes to trigger graded receptor activation from the acetylcholinebinding site while simultaneously restricting spatial flexibility of the receptor’s allostericvestibule. our findings reveal for the first time that a 7TmR’s allosteric vestibule controls theextent of receptor movement to govern a hierarchical order of G-protein coupling. This is a newconcept assigning a biological role to the allosteric vestibule for controlling fidelity of 7TmRsignalling.
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