A Cell-Permeable Inhibitor to Trap Gαq Proteins in the Empty Pocket Conformation

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 G alpha(q) signaling in a cellular context-dependent manner. Investigations into its mode of action reveal that BIM traps G alpha(q) in the empty pocket conformation by permitting GDP exit but interdicting GTP entry, a molecular mechanism not yet assigned to any other small molecule G alpha inhibitor to date. Our data show that G alpha proteins may be frozen'' pharmacologically in an intermediate conformation along their activation pathway and propose a pharmacological strategy to specifically silence G alpha subclasses with cell-permeable inhibitors.