A new molecular mechanism to engineer protean agonism at a G protein-coupled receptor

Anna De Min, Carlo Matera, Andreas Bock, Janine Holze, Jessica Kloeckner, Mathias Muth, Christian Traenkle, Marco De Amici, Terry Kenakin, Ulrike Holzgrabe, Clelia Dallanoce, Evi Kostenis, Klaus Mohr, Ramona Schrage

Research output: Contribution to journalArticle

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Abstract

Protean agonists are of great pharmacological interest as their behavior may change in magnitude and direction depending on the constitutive activity of a receptor. Yet, this intriguing phenomenon has been poorly described and understood, due to the lack of stable experimental systems and design strategies. In this study, we overcome both limitations: First, we demonstrate that modulation of the ionic strength in a defined experimental set-up allows for analysis of G protein-coupled receptor activation in the absence and presence of a specific amount of spontaneous receptor activity using the muscarinic M2 acetylcholine receptor as a model. Second, we employ this assay system to show that a dualsteric design principle, that is, molecular probes, carrying two pharmacophores to simultaneously adopt orthosteric and allosteric topography within a G protein-coupled receptor, may represent a novel approach to achieve protean agonism. We pinpoint three molecular requirements within dualsteric compounds that elicit protean agonism at the muscarinic M2 acetylcholine receptor. Using radioligandbinding and functional assays, we posit that dynamic ligand binding may be the mechanism underlying protean agonism of dualsteric ligands. Our findings provide both new mechanistic insights into the still enigmatic phenomenon of protean agonism and a rationale for the design of such compounds for a G protein-coupled receptor.

LanguageEnglish (US)
Pages348-356
Number of pages9
JournalMolecular pharmacology
Volume91
Issue number4
DOIs
StatePublished - Apr 1 2017

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G-Protein-Coupled Receptors
Cholinergic Receptors
Cholinergic Agents
Ligands
Molecular Probes
Osmolar Concentration
Research Design
Pharmacology

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

De Min, A., Matera, C., Bock, A., Holze, J., Kloeckner, J., Muth, M., ... Schrage, R. (2017). A new molecular mechanism to engineer protean agonism at a G protein-coupled receptor. Molecular pharmacology, 91(4), 348-356. DOI: 10.1124/mol.116.107276

A new molecular mechanism to engineer protean agonism at a G protein-coupled receptor. / De Min, Anna; Matera, Carlo; Bock, Andreas; Holze, Janine; Kloeckner, Jessica; Muth, Mathias; Traenkle, Christian; De Amici, Marco; Kenakin, Terry; Holzgrabe, Ulrike; Dallanoce, Clelia; Kostenis, Evi; Mohr, Klaus; Schrage, Ramona.

In: Molecular pharmacology, Vol. 91, No. 4, 01.04.2017, p. 348-356.

Research output: Contribution to journalArticle

De Min, A, Matera, C, Bock, A, Holze, J, Kloeckner, J, Muth, M, Traenkle, C, De Amici, M, Kenakin, T, Holzgrabe, U, Dallanoce, C, Kostenis, E, Mohr, K & Schrage, R 2017, 'A new molecular mechanism to engineer protean agonism at a G protein-coupled receptor' Molecular pharmacology, vol. 91, no. 4, pp. 348-356. DOI: 10.1124/mol.116.107276
De Min A, Matera C, Bock A, Holze J, Kloeckner J, Muth M et al. A new molecular mechanism to engineer protean agonism at a G protein-coupled receptor. Molecular pharmacology. 2017 Apr 1;91(4):348-356. Available from, DOI: 10.1124/mol.116.107276
De Min, Anna ; Matera, Carlo ; Bock, Andreas ; Holze, Janine ; Kloeckner, Jessica ; Muth, Mathias ; Traenkle, Christian ; De Amici, Marco ; Kenakin, Terry ; Holzgrabe, Ulrike ; Dallanoce, Clelia ; Kostenis, Evi ; Mohr, Klaus ; Schrage, Ramona. / A new molecular mechanism to engineer protean agonism at a G protein-coupled receptor. In: Molecular pharmacology. 2017 ; Vol. 91, No. 4. pp. 348-356
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