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Accuracy of genetic code translation and its orthogonal corruption by aminoglycosides and Mg2+ ions
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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.
2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 3, p. 1362-1374Article in journal (Refereed) Published
Abstract [en]

We studied the effects of aminoglycosides and changing Mg2+ ion concentration on the accuracy of initial codon selection by aminoacyl-tRNA in ternary complex with elongation factor Tu and GTP (T-3) on mRNA programmed ribosomes. Aminoglycosides decrease the accuracy by changing the equilibrium constants of 'monitoring bases' A1492, A1493 and G530 in 16S rRNA in favor of their 'activated' state by large, aminoglycoside-specific factors, which are the same for cognate and near-cognate codons. Increasing Mg2+ concentration decreases the accuracy by slowing dissociation of T-3 from its initial codon-and aminoglycoside-independent binding state on the ribosome. The distinct accuracy-corrupting mechanisms for aminoglycosides and Mg2+ ions prompted us to re-interpret previous biochemical experiments and functional implications of existing high resolution ribosome structures. We estimate the upper thermodynamic limit to the accuracy, the 'intrinsic selectivity' of the ribosome. We conclude that aminoglycosides do not alter the intrinsic selectivity but reduce the fraction of it that is expressed as the accuracy of initial selection. We suggest that induced fit increases the accuracy and speed of codon reading at unaltered intrinsic selectivity of the ribosome.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS , 2018. Vol. 46, no 3, p. 1362-1374
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-349357DOI: 10.1093/nar/gkx1256ISI: 000425294400033PubMedID: 29267976OAI: oai:DiVA.org:uu-349357DiVA, id: diva2:1202893
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilAvailable from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-05-02Bibliographically approved

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Pavlov, MichaelEhrenberg, Måns

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