The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

• Published in: Nature communications Vol. 3; no. 1; p. 1044
• Main Authors: Bock, Andreas, Merten, Nicole, Schrage, Ramona, Dallanoce, Clelia, Bätz, Julia, Klöckner, Jessica, Schmitz, Jens, Matera, Carlo, Simon, Katharina, Kebig, Anna, Peters, Lucas, Müller, Anke, Schrobang-Ley, Jasmin, Tränkle, Christian, Hoffmann, Carsten, De Amici, Marco, Holzgrabe, Ulrike, Kostenis, Evi, Mohr, Klaus
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 04.09.2012; Nature Pub. Group
• Subjects: Allosteric Site; GTP-Binding Proteins - metabolism; Humans; Protein Structure, Secondary; Protein Structure, Tertiary; Receptor, Muscarinic M2 - chemistry; Receptor, Muscarinic M2 - genetics; Receptor, Muscarinic M2 - metabolism; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2028

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.