Structural and Dynamical Basis of G Protein Inhibition by YM-254890 and FR900359: An Inhibitor in Action

J Chem Inf Model. 2019 Oct 28;59(10):4361-4373. doi: 10.1021/acs.jcim.9b00433. Epub 2019 Sep 26.


Specific inhibition of G proteins holds a great pharmacological promise to, e.g., target oncogenic Gq/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 Gq/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 Gq-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Depsipeptides / pharmacology*
  • GTP-Binding Proteins / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Peptides, Cyclic / pharmacology*
  • Protein Conformation


  • Depsipeptides
  • FR900359
  • Peptides, Cyclic
  • YM-254890
  • GTP-Binding Proteins