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The mechanism of error induction by the antibiotic viomycin provides insight into the fidelity mechanism of translation
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.ORCID iD: 0000-0002-4361-9554
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.ORCID iD: 0000-0002-3028-3270
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.ORCID iD: 0000-0002-7124-792X
2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e46124Article in journal (Refereed) Published
Abstract [en]

Applying pre-steady state kinetics to an Escherichia-coli-based reconstituted translation system, we have studied how the antibiotic viomycin affects the accuracy of genetic code reading. We find that viomycin binds to translating ribosomes associated with a ternary complex (TC) consisting of elongation factor Tu (EF-Tu), aminoacyl tRNA and GTP, and locks the otherwise dynamically flipping monitoring bases A1492 and A1493 into their active conformation. This effectively prevents dissociation of near- and non-cognate TCs from the ribosome, thereby enhancing errors in initial selection. Moreover, viomycin shuts down proofreading-based error correction. Our results imply a mechanism in which the accuracy of initial selection is achieved by larger backward rate constants toward TC dissociation rather than by a smaller rate constant for GTP hydrolysis for near- and non-cognate TCs. Additionally, our results demonstrate that translocation inhibition, rather than error induction, is the major cause of cell growth inhibition by viomycin.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD , 2019. Vol. 8, article id e46124
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-390687DOI: 10.7554/eLife.46124ISI: 000473013700001PubMedID: 31172942OAI: oai:DiVA.org:uu-390687DiVA, id: diva2:1342894
Funder
Swedish Research Council, 2018-05498Swedish Research Council, 2016-06264Knut and Alice Wallenberg Foundation, KAW 2011.0081Knut and Alice Wallenberg Foundation, KAW 2017.0055Carl Tryggers foundation , CTS 18: 338Wenner-Gren Foundations, UPD2017-0238Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved

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Holm, MikaelMandava, Chandra SekharEhrenberg, MånsSanyal, Suparna

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