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Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA.

Publication ,  Journal Article
Kumaraswami, M; Schuman, JT; Seo, SM; Kaatz, GW; Brennan, RG
Published in: Nucleic Acids Res
March 2009

MepR is a multidrug binding transcription regulator that represses expression of the Staphylococcus aureus multidrug efflux pump gene, mepA, as well as its own gene. MepR is induced by multiple cationic toxins, which are also substrates of MepA. In order to understand the gene regulatory and drug-binding mechanisms of MepR, we carried out biochemical, in vivo and structural studies. The 2.40 A resolution structure of drug-free MepR reveals the most open MarR family protein conformation to date, which will require a huge conformational change to bind cognate DNA. DNA-binding data show that MepR uses a dual regulatory binding mode as the repressor binds the mepA operator as a dimer of dimers, but binds the mepR operator as a single dimer. Alignment of the six half sites reveals the consensus MepR binding site, 5'-GTTAGAT-3'. 'Drug' binding studies show that MepR binds to ethidium and DAPI with comparable affinities (K(d) = 2.6 and 4.5 microM, respectively), but with significantly lower affinity to the larger rhodamine 6G (K(d) = 62.6 microM). Mapping clinically relevant or in vitro selected MepR mutants onto the MepR structure suggests that their defective repressor phenotypes are due to structural and allosteric defects.

Duke Scholars

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

March 2009

Volume

37

Issue

4

Start / End Page

1211 / 1224

Location

England

Related Subject Headings

  • Transcription Factors
  • Structural Homology, Protein
  • Staphylococcus aureus
  • Rhodamines
  • Protein Structure, Secondary
  • Operator Regions, Genetic
  • Mutation
  • Molecular Sequence Data
  • Models, Molecular
  • Membrane Transport Proteins
 

Citation

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Kumaraswami, M., Schuman, J. T., Seo, S. M., Kaatz, G. W., & Brennan, R. G. (2009). Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res, 37(4), 1211–1224. https://doi.org/10.1093/nar/gkn1046
Kumaraswami, Muthiah, Jason T. Schuman, Susan M. Seo, Glenn W. Kaatz, and Richard G. Brennan. “Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA.Nucleic Acids Res 37, no. 4 (March 2009): 1211–24. https://doi.org/10.1093/nar/gkn1046.
Kumaraswami M, Schuman JT, Seo SM, Kaatz GW, Brennan RG. Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res. 2009 Mar;37(4):1211–24.
Kumaraswami, Muthiah, et al. “Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA.Nucleic Acids Res, vol. 37, no. 4, Mar. 2009, pp. 1211–24. Pubmed, doi:10.1093/nar/gkn1046.
Kumaraswami M, Schuman JT, Seo SM, Kaatz GW, Brennan RG. Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res. 2009 Mar;37(4):1211–1224.
Journal cover image

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

March 2009

Volume

37

Issue

4

Start / End Page

1211 / 1224

Location

England

Related Subject Headings

  • Transcription Factors
  • Structural Homology, Protein
  • Staphylococcus aureus
  • Rhodamines
  • Protein Structure, Secondary
  • Operator Regions, Genetic
  • Mutation
  • Molecular Sequence Data
  • Models, Molecular
  • Membrane Transport Proteins