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Chem Biol. 2014 Jul 17;21(7):890-902. doi: 10.1016/j.chembiol.2014.06.003.

A cell-permeable inhibitor to trap Gαq proteins in the empty pocket conformation.

Author information

1
Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
2
Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.
3
Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany.
4
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
5
Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
6
Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
7
Eduard-Zintl-Institute of Inorganic and Physical Chemistry, Technische Universität Darmstadt, Alarich-Weiss-Straße 8, 64287 Darmstadt, Germany.
8
Institute of Physiology I, Life and Brain Center, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany.
9
Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, Brühler Straße 7, 53119 Bonn, Germany.
10
Institut des Maladies Métaboliques et Cardiovasculaires, Institut Nataional de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier, 31432 Toulouse, France.
11
Department of Pharmacology and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, United States.
12
Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany. Electronic address: kostenis@uni-bonn.de.

Abstract

In spite of the crucial role of heterotrimeric G proteins as molecular switches transmitting signals from G protein-coupled receptors, their selective manipulation with small molecule, cell-permeable inhibitors still remains an unmet challenge. Here, we report that the small molecule BIM-46187, previously classified as pan-G protein inhibitor, preferentially silences Gαq signaling in a cellular context-dependent manner. Investigations into its mode of action reveal that BIM traps Gαq in the empty pocket conformation by permitting GDP exit but interdicting GTP entry, a molecular mechanism not yet assigned to any other small molecule Gα inhibitor to date. Our data show that Gα proteins may be "frozen" pharmacologically in an intermediate conformation along their activation pathway and propose a pharmacological strategy to specifically silence Gα subclasses with cell-permeable inhibitors.

PMID:
25036778
PMCID:
PMC4337399
DOI:
10.1016/j.chembiol.2014.06.003
[Indexed for MEDLINE]
Free PMC Article
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