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

Journal article
Authors Daniel Tietze
D. Kaufmann
Alesia A. Tietze
A. Vo
R. Reher
G. Konig
F. Hausch
Published in Journal of Chemical Information and Modeling
Volume 59
Issue 10
Pages 4361-4373
ISSN 1549-9596
Publication year 2019
Published at Department of Chemistry and Molecular Biology
Wallenberg Centre for Molecular and Translational Medicine
Pages 4361-4373
Language en
Links dx.doi.org/10.1021/acs.jcim.9b00433
Keywords crystal-structure, nucleotide exchange, adp-ribosylation, chemical-shifts, drug discovery, side-chain, refinement, activation, transducin, accuracy, Pharmacology & Pharmacy, Chemistry, Computer Science
Subject categories Chemical Sciences, Pharmacology

Abstract

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.

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