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Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations.

Publication ,  Journal Article
Beggs, GA; Ayala, JC; Kavanaugh, LG; Read, TD; Hooks, GM; Schumacher, MA; Shafer, WM; Brennan, RG
Published in: Nucleic Acids Res
April 19, 2021

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.

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Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

April 19, 2021

Volume

49

Issue

7

Start / End Page

4155 / 4170

Location

England

Related Subject Headings

  • Repressor Proteins
  • Protein Binding
  • Neisseria gonorrhoeae
  • Mutation
  • Gene Expression Regulation, Bacterial
  • Drug Resistance, Multiple, Bacterial
  • Developmental Biology
  • DNA, Bacterial
  • Binding Sites
  • Bacterial Proteins
 

Citation

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Beggs, G. A., Ayala, J. C., Kavanaugh, L. G., Read, T. D., Hooks, G. M., Schumacher, M. A., … Brennan, R. G. (2021). Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations. Nucleic Acids Res, 49(7), 4155–4170. https://doi.org/10.1093/nar/gkab213
Beggs, Grace A., Julio C. Ayala, Logan G. Kavanaugh, Timothy D. Read, Grace M. Hooks, Maria A. Schumacher, William M. Shafer, and Richard G. Brennan. “Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations.Nucleic Acids Res 49, no. 7 (April 19, 2021): 4155–70. https://doi.org/10.1093/nar/gkab213.
Beggs GA, Ayala JC, Kavanaugh LG, Read TD, Hooks GM, Schumacher MA, et al. Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations. Nucleic Acids Res. 2021 Apr 19;49(7):4155–70.
Beggs, Grace A., et al. “Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations.Nucleic Acids Res, vol. 49, no. 7, Apr. 2021, pp. 4155–70. Pubmed, doi:10.1093/nar/gkab213.
Beggs GA, Ayala JC, Kavanaugh LG, Read TD, Hooks GM, Schumacher MA, Shafer WM, Brennan RG. Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations. Nucleic Acids Res. 2021 Apr 19;49(7):4155–4170.
Journal cover image

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

April 19, 2021

Volume

49

Issue

7

Start / End Page

4155 / 4170

Location

England

Related Subject Headings

  • Repressor Proteins
  • Protein Binding
  • Neisseria gonorrhoeae
  • Mutation
  • Gene Expression Regulation, Bacterial
  • Drug Resistance, Multiple, Bacterial
  • Developmental Biology
  • DNA, Bacterial
  • Binding Sites
  • Bacterial Proteins