Specific inhibition of G proteins holds a great pharmacological promise to, e.g., target oncogenic G proteins and can be achieved by the two natural products FR900359 (FR) and YM-254890 (YM). Unfortunately, recent rational-design-based approaches to address G proteins other than G subtypes were not successful mainly due to the conformational complexity of these new modalities-like compounds. Here, we report the water-derived NMR structure of YM, which strongly differs from the conformation of G-bound YM as found in the crystal structure. Reanalysis of the crystal structure suggests that the water-derived NMR structure of YM also represents a valid solution of the electron density. Extensive molecular dynamic simulations unveiled much higher binding affinities of the water-derived NMR structure compared to the original YM conformation of pdb 3ah8 . Employing a in-silico-designed, fast activating G protein conformation molecular dynamics data ultimately show how the inhibitor impairs the domain motion of the G protein necessary to hinder nucleotide exchange.