title: The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling.
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.
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bock
authors.forename: Nicole
authors.initials: N
authors.lastname: Merten
authors.forename: Ramona
authors.initials: R
authors.lastname: Schrage
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.forename: Julia
authors.initials: J
authors.lastname: Bätz
authors.forename: Jessica
authors.initials: J
authors.lastname: Klöckner
authors.forename: Jens
authors.initials: J
authors.lastname: Schmitz
authors.forename: Carlo
authors.initials: C
authors.lastname: Matera
authors.forename: Katharina
authors.initials: K
authors.lastname: Simon
authors.forename: Anna
authors.initials: A
authors.lastname: Kebig
authors.forename: Lucas
authors.initials: L
authors.lastname: Peters
authors.forename: Anke
authors.initials: A
authors.lastname: Müller
authors.forename: Jasmin
authors.initials: J
authors.lastname: Schrobang-Ley
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.forename: Carsten
authors.initials: C
authors.lastname: Hoffmann
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
mesh_terms: D000495:Allosteric Site; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043585:Receptor, Muscarinic M2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C487078:CHRM2 protein, human; D043585:Receptor, Muscarinic M2; D043562:Receptors, G-Protein-Coupled; C450520:seven-transmembrane G-protein-coupled receptor; D019204:GTP-Binding Proteins