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Nat Chem Biol. 2014 Jan;10(1):18-20. doi: 10.1038/nchembio.1384. Epub 2013 Nov 10.

Dynamic ligand binding dictates partial agonism at a G protein-coupled receptor.

Author information

1
1] Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany. [2].
2
Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany.
3
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany.
4
Bio-Imaging-Center/Rudolf-Virchow-Zentrum and Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
5
Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi', Università degli Studi di Milano, Milan, Italy.
6
Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany.

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.

PMID:
24212135
DOI:
10.1038/nchembio.1384
[Indexed for MEDLINE]

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