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

Andreas Bock, Nicole Merten, Ramona Schrage, Clelia Dallanoce, Julia Bätz, Jessica Klöckner, Jens Schmitz, Carlo Matera, Katharina Simon, Anna Kebig, Lucas Peters, Anke Müller, Jasmin Schrobang-Ley, Christian Tränkle, Carsten Hoffmann, Marco De Amici, Ulrike Holzgrabe, Evi Kostenis () and Klaus Mohr ()
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Andreas Bock: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn
Nicole Merten: Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Ramona Schrage: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn
Clelia Dallanoce: Sezione di Chimica Farmaceutica 'Pietro Pratesi', Università degli Studi di Milano
Julia Bätz: University of Würzburg
Jessica Klöckner: Institute of Pharmacy, University of Würzburg
Jens Schmitz: Institute of Pharmacy, University of Würzburg
Carlo Matera: Sezione di Chimica Farmaceutica 'Pietro Pratesi', Università degli Studi di Milano
Katharina Simon: Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Anna Kebig: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn
Lucas Peters: Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Anke Müller: Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Jasmin Schrobang-Ley: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn
Christian Tränkle: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn
Carsten Hoffmann: University of Würzburg
Marco De Amici: Sezione di Chimica Farmaceutica 'Pietro Pratesi', Università degli Studi di Milano
Ulrike Holzgrabe: Institute of Pharmacy, University of Würzburg
Evi Kostenis: Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Klaus Mohr: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: 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 M2 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.

Date: 2012
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DOI: 10.1038/ncomms2028

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