Flaviviridae viruses use a common molecular mechanism to escape nucleoside analogue inhibitors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F17%3AN0000097" target="_blank" >RIV/00027162:_____/17:N0000097 - isvavai.cz</a>

Alternative codes found

RIV/60077344:_____/17:00479566

Result on the web

<a href="http://www.sciencedirect.com/science/article/pii/S0006291X17305351?via%3Dihub" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0006291X17305351?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbrc.2017.03.068" target="_blank" >10.1016/j.bbrc.2017.03.068</a>

Result language

angličtina

Original language name

Flaviviridae viruses use a common molecular mechanism to escape nucleoside analogue inhibitors

Original language description

The RNA-dependent RNA polymerases of Flaviviridae viruses are crucial for replication. The Flaviviridae polymerase is organized into structural motifs (A-G), with motifs F, A, C and E containing interrogating, priming and catalytic substrate-interacting sites. Modified nucleoside analogues act as antiviral drugs by targeting Flaviviridae polymerases and integrating into the synthesized product causing premature termination. A threonine mutation of a conserved serine residue in motif B of Flaviviridae polymerases renders resistance to 2'-C-methylated nucleoside analogues. The mechanism how this single mutation causes Flaviviridae viruses to escape nucleoside analogues is not yet known. Given the pivotal position of the serine residue in motif B that supports motif F, we hypothesized the threonine mutation causes alterations in nucleoside exploration within the entry tunnel. Implementing a stochastic molecular software showed the all-atom 2'-C-methylated analogue reaction within the active sites of wild type and serine-threonine mutant polymerases from Hepacivirus and Flavivirus. Compared with the wild type, the serine-threonine mutant polymerases caused a significant decrease of analogue contacts with conserved interrogating residues in motif F and a displacement of metal ion cofactors. The simulations significantly showed that during the analogue exploration of the active site the hydrophobic methyl group in the serine-threonine mutant repels water-mediated hydrogen bonds with the 2'-C-methylated analogue, causing a concentration of water-mediated bonds at the substrate-interacting sites. Collectively, the data are an insight into a molecular escape mechanism by Flaviviridae viruses from 2'-C-methylated nucleoside analogue inhibitors. (C) 2017 Elsevier Inc. All rights reserved.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10607 - Virology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

ISSN

0006-291X

e-ISSN

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Volume of the periodical

492

Issue of the periodical within the volume

4

Country of publishing house

US - UNITED STATES

Number of pages

7

Pages from-to

652-658

UT code for WoS article

000413393300017

EID of the result in the Scopus database

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