A kinase bioscavenger provides antibiotic resistance by extremely tight substrate binding

Stanislav S. Terekhov, Yuliana A. Mokrushina, Anton S. Nazarov, Alexander Zlobin, Arthur Zalevsky, Gleb Bourenkov, Andrey Golovin, Alexey Belogurov, Ilya A. Osterman, Alexandra A. Kulikova, Vladimir A. Mitkevich, Hua Jane Lou, Benjamin E. Turk, Matthias Wilmanns, Ivan V. Smirnov, Sidney Altman, Alexander G. Gabibov

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17 Scopus citations

Abstract

Microbial communities are self-controlled by repertoires of lethal agents, the antibiotics. In their turn, these antibiotics are regulated by bioscavengers that are selected in the course of evolution. Kinase-mediated phosphorylation represents one of the general strategies for the emergence of antibiotic resistance. A new subfamily of AmiN-like kinases, isolated from the Siberian bear microbiome, inactivates antibiotic amicoumacin by phosphorylation. The nanomolar substrate affinity defines AmiN as a phosphotransferase with a unique catalytic efficiency proximal to the diffusion limit. Crystallographic analysis and multiscale simulations revealed a catalytically perfect mechanism providing phosphorylation exclusively in the case of a closed active site that counteracts substrate promiscuity. AmiN kinase is a member of the previously unknown subfamily representing the first evidence of a specialized phosphotransferase bioscavenger.

Original languageEnglish (US)
Article numbereaaz9861
JournalScience Advances
Volume6
Issue number26
DOIs
StatePublished - Jun 2020

ASJC Scopus subject areas

  • General

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  • AMICOUMACIN KINASE AMIN

    Terekhov, S. S. (Contributor), Mokrushina, Y. A. (Contributor), Nazarov, A. S. (Contributor), Zlobin, A. (Contributor), Zalevsky, A. (Contributor), Bourenkov, G. (Contributor), Golovin, A. (Contributor), Belogurov, A. (Contributor), Osterman, I. A. (Contributor), Kulikova, A. A. (Contributor), Mitkevich, V. A. (Contributor), Lou, H. J. (Contributor), Turk, B. E. (Contributor), Wilmanns, M. (Contributor), Smirnov, I. V. (Contributor), Altman, S. (Contributor) & Gabibov, A. G. (Contributor), Protein Data Bank (PDB), Jul 22 2020

    Dataset

  • Amicoumacin kinase AmiN in complex with ATP

    Terekhov, S. S. (Contributor), Mokrushina, Y. A. (Contributor), Nazarov, A. S. (Contributor), Zlobin, A. (Contributor), Zalevsky, A. (Contributor), Bourenkov, G. (Contributor), Golovin, A. (Contributor), Belogurov, A. (Contributor), Osterman, I. A. (Contributor), Kulikova, A. A. (Contributor), Mitkevich, V. A. (Contributor), Lou, H. J. (Contributor), Turk, B. E. (Contributor), Wilmanns, M. (Contributor), Smirnov, I. V. (Contributor), Altman, S. (Contributor) & Gabibov, A. G. (Contributor), Protein Data Bank (PDB), Jul 22 2020

    Dataset

  • Amicoumacin kinase hAmiN in complex with AMP-PNP, Ca2+ and Ami

    Terekhov, S. S. (Contributor), Mokrushina, Y. A. (Contributor), Nazarov, A. S. (Contributor), Zlobin, A. (Contributor), Zalevsky, A. (Contributor), Bourenkov, G. (Contributor), Golovin, A. (Contributor), Belogurov, A. (Contributor), Osterman, I. A. (Contributor), Kulikova, A. A. (Contributor), Mitkevich, V. A. (Contributor), Lou, H. J. (Contributor), Turk, B. E. (Contributor), Wilmanns, M. (Contributor), Smirnov, I. V. (Contributor), Altman, S. (Contributor) & Gabibov, A. G. (Contributor), Protein Data Bank (PDB), Jul 22 2020

    Dataset

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