title: Dynamic ligand binding dictates partial agonism at a G protein-coupled receptor.
abstract: We present a new concept of partial agonism at G protein-coupled receptors. We demonstrate the coexistence of two functionally distinct populations of the muscarinic M2 receptor stabilized by one dynamic ligand, which binds in two opposite orientations. The ratio of orientations determines the cellular response. Our concept allows predicting and virtually titrating ligand efficacy, which opens unprecedented opportunities for the design of drugs with graded activation of the biological system.
authors.affiliation: 1] Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany. [2].
authors.forename: Andreas
authors.initials: A
authors.lastname: Bock
authors.affiliation: Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Brian
authors.initials: B
authors.lastname: Chirinda
authors.affiliation: Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Krebs
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Messerer
authors.affiliation: Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bätz
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Muth
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi', Università degli Studi di Milano, Milan, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.affiliation: Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Dominika
authors.initials: D
authors.lastname: Klingenthal
authors.affiliation: Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.affiliation: Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi', Università degli Studi di Milano, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.affiliation: Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.affiliation: Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
mesh_terms: D001665:Binding Sites; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled