The G protein inhibitor YM-254890 is an allosteric glue

Given the prominence of G protein coupled receptors (GPCRs) as drug targets, targeting their immediate downstream effectors, G proteins, could be of immense therapeutic value. The discovery that the natural product YM-254890 (YM) can arrest uveal melanoma by specifically inhibiting constitutively active Gq/11without impacting other G protein families demonstrates the potential of this approach. However, efforts to find other G protein family-specific inhibitors have had limited success. Better understanding the mechanism of YM could facilitate efforts to develop other highly specific G protein inhibitors. We hypothesized that differences between the conformational distributions of various G proteins play an important role in determining he specificity of inhibitors like YM. To explore this hypothesis, we built Markov state models (MSMs) from molecular dynamics simulations of the G subunits of three different G proteins, as YM predominantly contacts G. We also modeled the heterotrimeric versions of these proteins where G is bound to the G{beta}{gamma} heterodimer. We find that YM-sensitive G proteins have a higher probability of adopting YM-bound-like conformations than insensitive variants. There is also strong allosteric coupling between the YM- and G{beta}{gamma}-binding interfaces of G. This allostery gives rise to positive cooperativity, wherein the presence of G{beta}{gamma} enhances preorganization for YM binding. We predict that YM acts as an "allosteric" glue that allosterically stabilizes the complex between G and G{beta}{gamma} despite the minimal contacts between YM and G{beta}{gamma}.