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Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2021 Apr 19; Vol. 49 (7), pp. 4155-4170. - Publication Year :
- 2021
-
Abstract
- Mutations within the mtrR gene are commonly found amongst multidrug resistant clinical isolates of Neisseria gonorrhoeae, which has been labelled a superbug by the Centers for Disease Control and Prevention. These mutations appear to contribute to antibiotic resistance by interfering with the ability of MtrR to bind to and repress expression of its target genes, which include the mtrCDE multidrug efflux transporter genes and the rpoH oxidative stress response sigma factor gene. However, the DNA-recognition mechanism of MtrR and the consensus sequence within these operators to which MtrR binds has remained unknown. In this work, we report the crystal structures of MtrR bound to the mtrCDE and rpoH operators, which reveal a conserved, but degenerate, DNA consensus binding site 5'-MCRTRCRN4YGYAYGK-3'. We complement our structural data with a comprehensive mutational analysis of key MtrR-DNA contacts to reveal their importance for MtrR-DNA binding both in vitro and in vivo. Furthermore, we model and generate common clinical mutations of MtrR to provide plausible biochemical explanations for the contribution of these mutations to multidrug resistance in N. gonorrhoeae. Collectively, our findings unveil key biological mechanisms underlying the global stress responses of N. gonorrhoeae.<br /> (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Binding Sites
Gene Expression Regulation, Bacterial
Mutation
Protein Binding
Bacterial Proteins genetics
Bacterial Proteins metabolism
DNA, Bacterial metabolism
Drug Resistance, Multiple, Bacterial genetics
Neisseria gonorrhoeae genetics
Neisseria gonorrhoeae metabolism
Repressor Proteins genetics
Repressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 49
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 33784401
- Full Text :
- https://doi.org/10.1093/nar/gkab213