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Structural basis for HflXr-mediated antibiotic resistance in Listeria monocytogenes

Koller, Timm O ; Turnbull, Kathryn J ; Vaitkevicius, Karolis ; Crowe-McAuliffe, Caillan ; Roghanian, Mohammad LU orcid ; Bulvas, Ondřej ; Nakamoto, Jose A LU orcid ; Kurata, Tatsuaki LU ; Julius, Christina LU and Atkinson, Gemma C LU , et al. (2022) In Nucleic Acids Research 50(19). p.11285-11300
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cryo-electron microscopy (cryo-EM), antibiotic resisitance, ribosome
in
Nucleic Acids Research
volume
50
issue
19
pages
11285 - 11300
publisher
Oxford University Press
external identifiers
  • scopus:85144543997
  • pmid:36300626
ISSN
1362-4962
DOI
10.1093/nar/gkac934
language
English
LU publication?
yes
additional info
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
id
0e1ac4d3-2e89-40e0-804c-919395f3f8a7
date added to LUP
2022-11-01 09:34:18
date last changed
2024-04-18 17:32:16
@article{0e1ac4d3-2e89-40e0-804c-919395f3f8a7,
  abstract     = {{<p>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.</p>}},
  author       = {{Koller, Timm O and Turnbull, Kathryn J and Vaitkevicius, Karolis and Crowe-McAuliffe, Caillan and Roghanian, Mohammad and Bulvas, Ondřej and Nakamoto, Jose A and Kurata, Tatsuaki and Julius, Christina and Atkinson, Gemma C and Johansson, Jörgen and Hauryliuk, Vasili and Wilson, Daniel N}},
  issn         = {{1362-4962}},
  keywords     = {{cryo-electron microscopy (cryo-EM); antibiotic resisitance; ribosome}},
  language     = {{eng}},
  number       = {{19}},
  pages        = {{11285--11300}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{Structural basis for HflXr-mediated antibiotic resistance in Listeria monocytogenes}},
  url          = {{http://dx.doi.org/10.1093/nar/gkac934}},
  doi          = {{10.1093/nar/gkac934}},
  volume       = {{50}},
  year         = {{2022}},
}