|Title||Structural and dynamical basis of G protein inhibition by YM-254890 and FR900359: An inhibitor in action|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Tietze D., Kaufmann D., Tietze A.A, Vo A., Reher R., Konig G., Hausch F.|
|Type of Article||Article|
|Keywords||accuracy; activation; adp-ribosylation; chemical-shifts; chemistry; Computer Science; crystal-structure; drug discovery; nucleotide exchange; Pharmacology & Pharmacy; refinement; side-chain; transducin|
Specific inhibition of G proteins holds a great pharmacological promise to, e.g., target oncogenic G(q/11) 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(q/11/14) 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(q)-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.