Given the prominence of G protein coupled receptors (GPCRs) as drug targets, targeting their immediate downstream effectors, G proteins, could be valuable as an alternative therapeutic strategy. The discovery that the natural product YM-254890 (YM) can arrest uveal melanoma by specifically inhibiting constitutively active Gq/11 demonstrates the potential of such an approach. However, efforts to find other G protein family-specific inhibitors have had limited success. Better understanding the inhibitory 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 protein isoforms play important roles in determining whether they are targeted by YM. We addressed this hypothesis by building Markov state models (MSMs) from molecular dynamics simulations of Gαsubunits and Gαβγ heterotrimers of three G protein isoforms. We find that in the absence of YM, YM-sensitive Gαsubunits have a higher probability of adopting conformations similar to the YM-bound state than YM-insensitive isoforms. There is also strong allosteric coupling between the YM- and Gβγ-binding interfaces of Gα. This allostery gives rise to positive cooperativity, wherein the presence of Gβγenhances preorganization for YM binding. We predict that YM acts as an "allosteric" glue that allosterically stabilizes the complex between Gαand Gβγ despite the minimal contacts between YM and Gβγ.