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A noncanonical binding site of linezolid revealed via molecular dynamics simulations

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Abstract

Linezolid, an antibiotic of oxazolidinone family, is a translation inhibitor. The mechanism of its action that consists in preventing the binding of aminoacyl-tRNA to the A-site of the large subunit of a ribosome was embraced on the basis of the X-ray structural analysis of the linezolid complexes with vacant bacterial ribosomes. However, the known structures of the linezolid complexes with bacterial ribosomes poorly explain the linezolid selectivity in suppression of protein biosynthesis, depending on the amino acid sequence of the nascent peptide. In the present study the most probable structure of the linezolid complex with a E. coli ribosome in the A,A/P,P-state that is in line with the results of biochemical studies of linezolid action has been obtained by molecular dynamics simulation methods.

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Acknowledgements

We thank Professor A. A. Bogdanov for active support of the research and associate professor E. I. Danilina for assistance in preparation of the article. We thank the Research Computing Center of Lomonosov Moscow State University for the opportunity to compute molecular dynamics using the “Lomonosov-II” supercomputer. This research was supported by the Russian Science Foundation (Project No. 18-74-00022, interaction of antibiotics with binding sites forming in a dynamically manner), and by the Government of the Russian Federation (Resolution No. 211 dated 16.03.2013, Contract No. 02.A03.21.0011).

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  1. South Ural State University, Chelyabinsk, Russia, 454080

    G. I. Makarov & T. M. Makarova

  2. Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia, 119991

    T. M. Makarova

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Makarov, G.I., Makarova, T.M. A noncanonical binding site of linezolid revealed via molecular dynamics simulations. J Comput Aided Mol Des 34, 281–291 (2020). https://doi.org/10.1007/s10822-019-00269-x

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