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Structural basis for HflXr-mediated antibiotic resistance in Listeria monocytogenes
Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, Hamburg, Germany.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, Hamburg, Germany.
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2022 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, no 19, p. 11285-11300Article in journal (Refereed) Published
Abstract [en]

HflX is a ubiquitous bacterial GTPase that splits and recycles stressed ribosomes. In addition to HflX, Listeria monocytogenes contains a second HflX homolog, HflXr. Unlike HflX, HflXr confers resistance to macrolide and lincosamide antibiotics by an experimentally unexplored mechanism. Here, we have determined cryo-EM structures of L. monocytogenes HflXr-50S and HflX-50S complexes as well as L. monocytogenes 70S ribosomes in the presence and absence of the lincosamide lincomycin. While the overall geometry of HflXr on the 50S subunit is similar to that of HflX, a loop within the N-terminal domain of HflXr, which is two amino acids longer than in HflX, reaches deeper into the peptidyltransferase center. Moreover, unlike HflX, the binding of HflXr induces conformational changes within adjacent rRNA nucleotides that would be incompatible with drug binding. These findings suggest that HflXr confers resistance using an allosteric ribosome protection mechanism, rather than by simply splitting and recycling antibiotic-stalled ribosomes.

Place, publisher, year, edition, pages
Oxford University Press, 2022. Vol. 50, no 19, p. 11285-11300
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-202075DOI: 10.1093/nar/gkac934ISI: 000873820100001PubMedID: 36300626Scopus ID: 2-s2.0-85144543997OAI: oai:DiVA.org:umu-202075DiVA, id: diva2:1723496
Funder
Swedish Research Council, 2017-03783Swedish Research Council, 2021-01146Swedish Research Council, 2019-01085Swedish Research Council, 2020-020053Olle Engkvists stiftelseRagnar Söderbergs stiftelseKnut and Alice Wallenberg Foundation, 2020-0037Available from: 2023-01-03 Created: 2023-01-03 Last updated: 2023-01-03Bibliographically approved

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Turnbull, Kathryn JaneVaitkevicius, KarolisRoghanian, MohammadKurata, TatsuakiJulius, ChristinaJohansson, JörgenHauryliuk, Vasili

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Turnbull, Kathryn JaneVaitkevicius, KarolisRoghanian, MohammadKurata, TatsuakiJulius, ChristinaJohansson, JörgenHauryliuk, Vasili
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Molecular Infection Medicine Sweden (MIMS)Umeå Centre for Microbial Research (UCMR)Department of Molecular Biology (Faculty of Medicine)
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