The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 Å resolution

MarR is a regulator of multiple antibiotic resistance in Escherichia coli. It is the prototypical member of the MarR family of regulatory proteins found in bacteria and archaea that play important roles in the development of antibiotic resistance, a global health problem. Here we describe the crystal structure of the MarR protein, determined at a resolution of 2.3 Å. This is the first reported crystal structure of a member of this newly-described protein family. The structure shows MarR as a dimer with each subunit containing a winged-helix DNA binding motif.

[1]  S. Levy,et al.  Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon , 1997, Antimicrobial agents and chemotherapy.

[2]  P. Miller,et al.  Overlaps and parallels in the regulation of intrinsic multiple‐antibiotic resistance in Escherichia coli , 1996, Molecular microbiology.

[3]  Stephen K. Burley,et al.  Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding , 2000, Nature.

[4]  E J Dodson,et al.  Collaborative Computational Project, number 4: providing programs for protein crystallography. , 1997, Methods in enzymology.

[5]  S. Levy,et al.  The mar regulon: multiple resistance to antibiotics and other toxic chemicals. , 1999, Trends in microbiology.

[6]  P. Miller,et al.  The Salmonella typhimurium mar locus: molecular and genetic analyses and assessment of its role in virulence , 1997, Journal of bacteriology.

[7]  S. Levy,et al.  Identification for mar mutants among quinolone-resistant clinical isolates of Escherichia coli , 1996, Antimicrobial agents and chemotherapy.

[8]  Thomas C. Terwilliger,et al.  Automated MAD and MIR structure solution , 1999, Acta crystallographica. Section D, Biological crystallography.

[9]  S. Levy,et al.  Differential Expression of over 60 Chromosomal Genes in Escherichia coli by Constitutive Expression of MarA , 2000, Journal of bacteriology.

[10]  T. A. Jones,et al.  Databases in protein crystallography. , 1998, Acta crystallographica. Section D, Biological crystallography.

[11]  S. Levy,et al.  Alteration of the Repressor Activity of MarR, the Negative Regulator of the Escherichia coli marRAB Locus, by Multiple Chemicals In Vitro , 1999, Journal of bacteriology.

[12]  N. Guex,et al.  SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modeling , 1997, Electrophoresis.

[13]  D. Ringe,et al.  Structure of the metal-ion-activated diphtheria toxin repressor/ tox operator complex , 1998, Nature.

[14]  S. Levy,et al.  A soxRS-Constitutive Mutation Contributing to Antibiotic Resistance in a Clinical Isolate of Salmonella enterica (Serovar Typhimurium) , 2001, Antimicrobial Agents and Chemotherapy.

[15]  G J Barton,et al.  ALSCRIPT: a tool to format multiple sequence alignments. , 1993, Protein engineering.

[16]  S. Levy,et al.  Non-Target Gene Mutations in the Development of Fluoroquinolone Resistance in Escherichia coli , 2000, Antimicrobial Agents and Chemotherapy.

[17]  J. Rosner,et al.  Binding of purified multiple antibiotic-resistance repressor protein (MarR) to mar operator sequences. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  W G Hol,et al.  Motion of the DNA-binding Domain with Respect to the Core of the Diphtheria Toxin Repressor (DtxR) Revealed in the Crystal Structures of Apo- and Holo-DtxR* , 1998, The Journal of Biological Chemistry.

[19]  S K Burley,et al.  Winged helix proteins. , 2000, Current opinion in structural biology.

[20]  S. Burley,et al.  Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5 , 1993, Nature.

[21]  E. Fraenkel,et al.  Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. , 1999, Genes & development.

[22]  S. Levy,et al.  Salicylate induction of antibiotic resistance in Escherichia coli: activation of the mar operon and a mar-independent pathway , 1993, Journal of bacteriology.

[23]  A. Brooun,et al.  Purification and Ligand Binding of EmrR, a Regulator of a Multidrug Transporter , 1999, Journal of bacteriology.

[24]  F. Notka,et al.  In Vivo Increase in Resistance to Ciprofloxacin inEscherichia coli Associated with Deletion of the C-Terminal Part of MarR , 2000, Antimicrobial Agents and Chemotherapy.

[25]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[26]  S. Levy,et al.  Characterization of MarR Superrepressor Mutants , 1999, Journal of bacteriology.

[27]  S. Levy,et al.  Overexpression of the marA or soxSRegulatory Gene in Clinical Topoisomerase Mutants ofEscherichia coli , 1998, Antimicrobial Agents and Chemotherapy.

[28]  K. Jair,et al.  Autoactivation of the marRAB multiple antibiotic resistance operon by the MarA transcriptional activator in Escherichia coli , 1996, Journal of bacteriology.

[29]  Jeffrey H. Miller.  Experiments in molecular genetics , 1972 .

[30]  H. Nikaido,et al.  Multiple antibiotic resistance and efflux. , 1998, Current opinion in microbiology.

[31]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[32]  Ann M Stock,et al.  The DNA-binding domain of OmpR: crystal structures of a winged helix transcription factor. , 1997, Structure.

[33]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[34]  S. Levy,et al.  Mutational analysis of MarR, the negative regulator of marRAB expression in Escherichia coli, suggests the presence of two regions required for DNA binding , 2000, Molecular microbiology.

[35]  T. Köhler,et al.  In Vivo Emergence of Multidrug-Resistant Mutants ofPseudomonas aeruginosa Overexpressing the Active Efflux System MexA-MexB-OprM , 1999, Antimicrobial Agents and Chemotherapy.