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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Cyclohexanes / chemistry
  • Cyclohexanes / metabolism*
  • Cyclohexanes / pharmacology*
  • Dimerization
  • GTP-Binding Protein alpha Subunits, Gq-G11 / antagonists & inhibitors*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / chemistry*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Humans
  • Models, Molecular
  • Permeability
  • Protein Conformation / drug effects
  • Pyrazines / chemistry
  • Pyrazines / metabolism*
  • Pyrazines / pharmacology*
  • Signal Transduction / drug effects


  • 7-(2-amino-1-oxo-3-thio-propyl)-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-(1,2a)-pyrazine dimer, hydrochloride
  • Cyclohexanes
  • Pyrazines
  • GTP-Binding Protein alpha Subunits, Gq-G11