Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome

Tereshchenkov, Andrey G.; Dobosz-Bartoszek, Malgorzata; Osterman, Ilya A.; Marks, James; Sergeeva, Vasilina A.; Kasatsky, Pavel; Komarova (Andreyanova), Ekaterina S.; Stavrianidi, Andrey N.; Rodin, Igor A.; Konevega, Andrey L.; Sergiev, Petr V.; Sumbatyan, Natalia V.; Mankin, Alexander S.; Bogdanov, Alexey A.; Polikanov, Yury S.

doi:10.1016/j.jmb.2018.01.016

Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome

Journal Article · Fri Feb 02 00:00:00 EST 2018 · Journal of Molecular Biology

DOI:https://doi.org/10.1016/j.jmb.2018.01.016· OSTI ID:1434725

Tereshchenkov, Andrey G. ^[1]; Dobosz-Bartoszek, Malgorzata ^[2]; Osterman, Ilya A. ^[3]; Marks, James ^[2]; Sergeeva, Vasilina A. ^[4]; Kasatsky, Pavel ^[5]; Komarova (Andreyanova), Ekaterina S. ^[6]; Stavrianidi, Andrey N. ^[1]; Rodin, Igor A. ^[1]; Konevega, Andrey L. ^[7]; Sergiev, Petr V. ^[3]; Sumbatyan, Natalia V. ^[1]; Mankin, Alexander S. ^[2]; Bogdanov, Alexey A. ^[1]; Polikanov, Yury S. ^[2]

Lomonosov Moscow State Univ., Moscow (Russia)
Univ. of Illinois, Chicago, IL (United States)
Lomonosov Moscow State Univ., Moscow (Russia); Skolkovo Inst. of Science and Technology (Russia)
Lomonosov Moscow State Univ., Moscow (Russia); Russian Academy of Medical Sciences, Moscow (Russia)
National Research Centre (NRC), Moscow (Russia). Kurchatov Inst. (NRCKI)
Skolkovo Inst. of Science and Technology (Russia); Lomonosov Moscow State Univ., Moscow (Russia)
National Research Centre (NRC), Moscow (Russia). Kurchatov Inst. (NRCKI); Peter the Great St. Petersburg Polytechnic Univ., Saint Petersburg (Russia)

Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. We report the L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Illinois State; National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Russian Foundation for Basic Research; Russian Science Foundation (RSF); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1434725

Journal Information:: Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 6 Vol. 430; ISSN 0022-2836

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
X-ray structure
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protein synthesis
ribosome

Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome

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References (43)

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