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

doi:10.1126/sciadv.aaz9861

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

Life Sciences, School of (SOLS)

Research output: Contribution to journal › Article › peer-review

15 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 language	English (US)
Article number	eaaz9861
Journal	Science Advances
Volume	6
Issue number	26
DOIs	https://doi.org/10.1126/sciadv.aaz9861
State	Published - Jun 2020

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10.1126/sciadv.aaz9861

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Terekhov, S. S., Mokrushina, Y. A., Nazarov, A. S., Zlobin, A., Zalevsky, A., Bourenkov, G., Golovin, A., Belogurov, A., Osterman, I. A., Kulikova, A. A., Mitkevich, V. A., Lou, H. J., Turk, B. E., Wilmanns, M., Smirnov, I. V., Altman, S., & Gabibov, A. G. (2020). A kinase bioscavenger provides antibiotic resistance by extremely tight substrate binding. Science Advances, 6(26), Article eaaz9861. https://doi.org/10.1126/sciadv.aaz9861

Terekhov, SS, Mokrushina, YA, Nazarov, AS, Zlobin, A, Zalevsky, A, Bourenkov, G, Golovin, A, Belogurov, A, Osterman, IA, Kulikova, AA, Mitkevich, VA, Lou, HJ, Turk, BE, Wilmanns, M, Smirnov, IV, Altman, S & Gabibov, AG 2020, 'A kinase bioscavenger provides antibiotic resistance by extremely tight substrate binding', Science Advances, vol. 6, no. 26, eaaz9861. https://doi.org/10.1126/sciadv.aaz9861

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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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved.",

year = "2020",

month = jun,

doi = "10.1126/sciadv.aaz9861",

language = "English (US)",

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journal = "Science Advances",

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AU - Mokrushina, Yuliana A.

AU - Nazarov, Anton S.

AU - Zlobin, Alexander

AU - Zalevsky, Arthur

AU - Bourenkov, Gleb

AU - Golovin, Andrey

AU - Belogurov, Alexey

AU - Osterman, Ilya A.

AU - Kulikova, Alexandra A.

AU - Mitkevich, Vladimir A.

AU - Lou, Hua Jane

AU - Turk, Benjamin E.

AU - Wilmanns, Matthias

AU - Smirnov, Ivan V.

AU - Altman, Sidney

AU - Gabibov, Alexander G.

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

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A kinase bioscavenger provides antibiotic resistance by extremely tight substrate binding

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Amicoumacin kinase AmiN in complex with ATP

Amicoumacin kinase AmiN in complex with AMP-PNP, Mg2+ and Ami

AMICOUMACIN KINASE AMIN

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A kinase bioscavenger provides antibiotic resistance by extremely tight substrate binding

Abstract

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Datasets

Amicoumacin kinase AmiN in complex with ATP

Amicoumacin kinase AmiN in complex with AMP-PNP, Mg2+ and Ami

AMICOUMACIN KINASE AMIN

Cite this