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Antibiotic resistance ABCF proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Tartu, Estonia.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 7, p. 3753-3763Article in journal (Refereed) Published
Abstract [en]

Several ATPases in the ATP-binding cassette F (ABCF) family confer resistance to macrolides, lincosamides and streptogramins (MLS) antibiotics. MLS are structurally distinct classes, but inhibit a common target: the peptidyl transferase (PTC) active site of the ribosome. Antibiotic resistance (ARE) ABCFs have recently been shown to operate through direct ribosomal protection, but the mechanistic details of this resistance mechanism are lacking. Using a reconstituted translational system, we dissect the molecular mechanism of Staphylococcus haemolyticus VgaA(LC) and Enterococcus faecalis LsaA on the ribosome. We demonstrate that VgaA(LC) is an NTPase that operates as a molecular machine strictly requiring NTP hydrolysis (not just NTP binding) for antibiotic protection. Moreover, when bound to the ribosome in the NTP-bound form, hydrolytically inactive EQ(2) ABCF ARE mutants inhibit peptidyl transferase activity, suggesting a direct interaction between the ABCF ARE and the PTC. The likely structural candidate responsible for antibiotic displacement by wild type ABCF AREs, and PTC inhibition by the EQ(2) mutant, is the extended inter-ABC domain linker region. Deletion of the linker region renders wild type VgaA(LC) inactive in antibiotic protection and the EQ(2) mutant inactive in PTC inhibition.

Place, publisher, year, edition, pages
Oxford University Press, 2018. Vol. 46, no 7, p. 3753-3763
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:umu:diva-147824DOI: 10.1093/nar/gky050ISI: 000431137900041PubMedID: 29415157OAI: oai:DiVA.org:umu-147824DiVA, id: diva2:1207133
Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-06-09Bibliographically approved

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Murina, VictoriiaKasari, MarjeHauryliuk, VasiliAtkinson, Gemma C.

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