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

Artikel i vetenskaplig tidskrift
Författare Daniel Tietze
D. Kaufmann
Alesia A. Tietze
A. Vo
R. Reher
G. Konig
F. Hausch
Publicerad i Journal of Chemical Information and Modeling
Volym 59
Nummer/häfte 10
Sidor 4361-4373
ISSN 1549-9596
Publiceringsår 2019
Publicerad vid Institutionen för kemi och molekylärbiologi
Wallenberg Centre for Molecular and Translational Medicine
Sidor 4361-4373
Språk en
Länkar dx.doi.org/10.1021/acs.jcim.9b00433
Ämnesord crystal-structure, nucleotide exchange, adp-ribosylation, chemical-shifts, drug discovery, side-chain, refinement, activation, transducin, accuracy, Pharmacology & Pharmacy, Chemistry, Computer Science
Ämneskategorier Kemi, Farmakologi

Sammanfattning

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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