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PDBsum entry 1lnw

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protein Protein-protein interface(s) links
Transcription repressor PDB id
1lnw
Jmol
Contents
Protein chains
(+ 0 more) 141 a.a. *
130 a.a. *
Waters ×214
* Residue conservation analysis
PDB id:
1lnw
Name: Transcription repressor
Title: Crystal structure of the mexr repressor of the mexab-oprm multidrug efflux operon of pseudomonas aeruginosa
Structure: Multidrug resistance operon repressor. Chain: a, b, c, d, e, f, g, h. Synonym: mexr. Engineered: yes
Source: Pseudomonas aeruginosa. Organism_taxid: 287. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
2.10Å     R-factor:   0.242     R-free:   0.294
Authors: D.C.Lim,K.Poole,N.C.J.Strynadka
Key ref:
D.Lim et al. (2002). Crystal structure of the MexR repressor of the mexRAB-oprM multidrug efflux operon of Pseudomonas aeruginosa. J Biol Chem, 277, 29253-29259. PubMed id: 12034710 DOI: 10.1074/jbc.M111381200
Date:
03-May-02     Release date:   11-Sep-02    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P52003  (MEXR_PSEAE) -  Multidrug resistance operon repressor
Seq:
Struc:
147 a.a.
141 a.a.
Protein chains
Pfam   ArchSchema ?
P52003  (MEXR_PSEAE) -  Multidrug resistance operon repressor
Seq:
Struc:
147 a.a.
130 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   1 term 
  Biological process     negative regulation of transmembrane transport   5 terms 
  Biochemical function     transcription regulatory region DNA binding     5 terms  

 

 
DOI no: 10.1074/jbc.M111381200 J Biol Chem 277:29253-29259 (2002)
PubMed id: 12034710  
 
 
Crystal structure of the MexR repressor of the mexRAB-oprM multidrug efflux operon of Pseudomonas aeruginosa.
D.Lim, K.Poole, N.C.Strynadka.
 
  ABSTRACT  
 
MexR is a member of the MarR family of bacterial transcriptional regulators and is the repressor for the MexAB-OprM operon, which encodes a tripartite multidrug efflux system in Pseudomonas aeruginosa. Mutations in MexR result in increased resistance to multiple antibiotics due to overexpression of this efflux system. We have determined the crystal structure of MexR to 2.1-A resolution in the absence of effector. The four copies of the MexR dimer in the asymmetric unit are observed in multiple conformations. Analysis of these conformational states in the context of a model of the MexR-DNA complex proposed in this study suggests that an effector-induced conformational change may inhibit DNA binding by reducing the spacing of the DNA binding domains. The inhibited conformation is exhibited by one of the four MexR dimers, which contains an ordered C-terminal tail from a neighboring monomer inserted between its DNA binding domains and which we propose may resemble the MexR-effector complex. Our results indicate that MexR may differ from the other described member of this family, MarR, in the nature of its effector, mode of DNA binding, and mechanism of regulation.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Overall structure of the MexR dimer. a, MexR dimer in ribbon representation. The secondary structure elements are labeled and colored individually in the monomer on the right. The winged helix domain (colored blue in the monomer on the left) consists of 2 (H1)- 1 (S1)- 3 (H2)- 4 (H3, recognition helix)- 2 (S2)-W1 (wing)- 3 (S3), where the terminology used by Gajiwala and Burley (24) is given in brackets. The N and C termini are labeled N and C, respectively. b, MexR dimer shown in similar orientation as in a and with a GRASP (43) molecular surface representation of one subunit highlighting the hydrophobic dimerization interface. Low, medium, and high hydrophobic potentials are colored gray, yellow, and green, respectively. The second subunit is shown in ribbon respresentation (magenta).
Figure 3.
Fig. 3. Proposed mechanism of regulation of MexR. a, molecular modeling of MexR-DNA complex. The MexR dimer CD (ribbon representation) depicts the "open" or DNA-bound conformation. The DNA molecule is shown in stick representation, with the inverted repeats colored green and highlighted by thick rendering. Residues on MexR which correspond to the MarR residues observed to be in contact with salicylate (23) are shown in stick rendering. b, insertion of the C-terminal tail (residues 140-147 shown with magenta carbons) from chain C in between the DNA binding domains results in a "closed" conformation depicted by dimer AB (ribbon representation), in which the reduced spacing between the DNA binding domains is incompatible with the spacing of the inverted repeats (green with thick rendering) of the operator. SigmaA-weighted 2F[o] F[c] electron density (29) is contoured at 1 to 2.1 Å around the C-terminal tail. The electron density object was created in O (44). c, close-up view of the interactions between the C-terminal tail of monomer C (magenta) with side chains on monomer A. d, close-up view of the interactions between the C-terminal tail of monomer C (magenta) with the side chains on monomer B. Water molecules are shown as red spheres in c and d. e, electrophoretic mobility shift assays of DNA binding by SeMet MexR with and without treatment with Hinc II restriction endonuclease. All samples contained 247 ng of a 28-bp DNA oligonucleotide with the sequence 5'ATTTTAGTT GACCTTATCAACCTTGTTT (the HincII site is in bold with the cleavage site indicated by ) corresponding to the MexR binding site II identified by previous footprinting studies (26). The DNA in lanes 3 and 4 were digested with HincII for 1 h and 40 min at 37 °C. Prior to loading onto the gel, 12.8 µg of SeMet-substituted MexR protein were added to samples in lanes 2 and 4.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 29253-29259) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20421944 A.Fernandez, D.Lechardeur, A.Derré-Bobillot, E.Couvé, P.Gaudu, and A.Gruss (2010).
Two coregulated efflux transporters modulate intracellular heme and protoporphyrin IX availability in Streptococcus agalactiae.
  PLoS Pathog, 6, e1000860.  
20095047 C.Andrésen, S.Jalal, D.Aili, Y.Wang, S.Islam, A.Jarl, B.Liedberg, B.Wretlind, L.G.Mårtensson, and M.Sunnerhagen (2010).
Critical biophysical properties in the Pseudomonas aeruginosa efflux gene regulator MexR are targeted by mutations conferring multidrug resistance.
  Protein Sci, 19, 680-692.  
20616806 H.Chen, C.Yi, J.Zhang, W.Zhang, Z.Ge, C.G.Yang, and C.He (2010).
Structural insight into the oxidation-sensing mechanism of the antibiotic resistance of regulator MexR.
  EMBO Rep, 11, 685-690.
PDB code: 3mex
20580544 H.Wade (2010).
MD recognition by MDR gene regulators.
  Curr Opin Struct Biol, 20, 489-496.  
20716550 I.C.Perera, and A.Grove (2010).
Molecular mechanisms of ligand-mediated attenuation of DNA binding by MarR family transcriptional regulators.
  J Mol Cell Biol, 2, 243-254.  
19897647 I.I.Mustakhimov, A.S.Reshetnikov, A.S.Glukhov, V.N.Khmelenina, M.G.Kalyuzhnaya, and Y.A.Trotsenko (2010).
Identification and characterization of EctR1, a new transcriptional regulator of the ectoine biosynthesis genes in the halotolerant methanotroph Methylomicrobium alcaliphilum 20Z.
  J Bacteriol, 192, 410-417.  
20513431 K.J.McLaughlin, C.M.Strain-Damerell, K.Xie, D.Brekasis, A.S.Soares, M.S.Paget, and C.L.Kielkopf (2010).
Structural basis for NADH/NAD+ redox sensing by a Rex family repressor.
  Mol Cell, 38, 563-575.
PDB codes: 3ikt 3ikv 3il2
20379743 S.Schielke, M.Frosch, and O.Kurzai (2010).
Virulence determinants involved in differential host niche adaptation of Neisseria meningitidis and Neisseria gonorrhoeae.
  Med Microbiol Immunol, 199, 185-196.  
20094649 V.Duarte, and J.M.Latour (2010).
PerR vs OhrR: selective peroxide sensing in Bacillus subtilis.
  Mol Biosyst, 6, 316-323.  
20421503 Y.M.Chang, W.Y.Jeng, T.P.Ko, Y.J.Yeh, C.K.Chen, and A.H.Wang (2010).
Structural study of TcaR and its complexes with multiple antibiotics from Staphylococcus epidermidis.
  Proc Natl Acad Sci U S A, 107, 8617-8622.
PDB codes: 3kp2 3kp3 3kp4 3kp5 3kp6 3kp7
19586910 C.B.Poor, P.R.Chen, E.Duguid, P.A.Rice, and C.He (2009).
Crystal structures of the reduced, sulfenic acid, and mixed disulfide forms of SarZ, a redox active global regulator in Staphylococcus aureus.
  J Biol Chem, 284, 23517-23524.
PDB codes: 3hrm 3hse 3hsr
  19255465 C.E.Nichols, S.Sainsbury, J.Ren, T.S.Walter, A.Verma, D.K.Stammers, N.J.Saunders, and R.J.Owens (2009).
The structure of NMB1585, a MarR-family regulator from Neisseria meningitidis.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 204-209.
PDB code: 3g3z
19154333 C.Sala, A.Haouz, F.A.Saul, I.Miras, I.Rosenkrands, P.M.Alzari, and S.T.Cole (2009).
Genome-wide regulon and crystal structure of BlaI (Rv1846c) from Mycobacterium tuberculosis.
  Mol Microbiol, 71, 1102-1116.
PDB code: 2g9w
19129225 M.Kumaraswami, J.T.Schuman, S.M.Seo, G.W.Kaatz, and R.G.Brennan (2009).
Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA.
  Nucleic Acids Res, 37, 1211-1224.
PDB code: 3eco
19400792 S.Schielke, C.Huebner, C.Spatz, V.Nägele, N.Ackermann, M.Frosch, O.Kurzai, and A.Schubert-Unkmeir (2009).
Expression of the meningococcal adhesin NadA is controlled by a transcriptional regulator of the MarR family.
  Mol Microbiol, 72, 1054-1067.  
19509310 T.Kumarevel, T.Tanaka, T.Umehara, and S.Yokoyama (2009).
ST1710-DNA complex crystal structure reveals the DNA binding mechanism of the MarR family of regulators.
  Nucleic Acids Res, 37, 4723-4735.
PDB codes: 3gez 3gf2 3gfi 3gfj 3gfl 3gfm
19788177 Z.Ma, F.E.Jacobsen, and D.P.Giedroc (2009).
Coordination chemistry of bacterial metal transport and sensing.
  Chem Rev, 109, 4644-4681.  
18757728 H.Chen, J.Hu, P.R.Chen, L.Lan, Z.Li, L.M.Hicks, A.R.Dinner, and C.He (2008).
The Pseudomonas aeruginosa multidrug efflux regulator MexR uses an oxidation-sensing mechanism.
  Proc Natl Acad Sci U S A, 105, 13586-13591.  
18812515 M.S.Wilke, M.Heller, A.L.Creagh, C.A.Haynes, L.P.McIntosh, K.Poole, and N.C.Strynadka (2008).
The crystal structure of MexR from Pseudomonas aeruginosa in complex with its antirepressor ArmR.
  Proc Natl Acad Sci U S A, 105, 14832-14837.
PDB code: 3ech
17545281 D.M.Daigle, L.Cao, S.Fraud, M.S.Wilke, A.Pacey, R.Klinoski, N.C.Strynadka, C.R.Dean, and K.Poole (2007).
Protein modulator of multidrug efflux gene expression in Pseudomonas aeruginosa.
  J Bacteriol, 189, 5441-5451.  
17675388 G.Fiorentino, R.Ronca, R.Cannio, M.Rossi, and S.Bartolucci (2007).
MarR-like transcriptional regulator involved in detoxification of aromatic compounds in Sulfolobus solfataricus.
  J Bacteriol, 189, 7351-7360.  
17576674 J.Boudet, V.Duval, H.Van Melckebeke, M.Blackledge, A.Amoroso, B.Joris, and J.P.Simorre (2007).
Conformational and thermodynamic changes of the repressor/DNA operator complex upon monomerization shed new light on regulation mechanisms of bacterial resistance against beta-lactam antibiotics.
  Nucleic Acids Res, 35, 4384-4395.
PDB code: 2p7c
18042459 K.J.Newberry, M.Fuangthong, W.Panmanee, S.Mongkolsuk, and R.G.Brennan (2007).
Structural mechanism of organic hydroperoxide induction of the transcription regulator OhrR.
  Mol Cell, 28, 652-664.
PDB codes: 2pex 2pfb
17357153 K.Miyazono, M.Tsujimura, Y.Kawarabayasi, and M.Tanokura (2007).
Crystal structure of an archaeal homologue of multidrug resistance repressor protein, EmrR, from hyperthermophilic archaea Sulfolobus tokodaii strain 7.
  Proteins, 67, 1138-1146.
PDB code: 2gxg
17586628 S.Y.Oh, J.H.Shin, and J.H.Roe (2007).
Dual role of OhrR as a repressor and an activator in response to organic hydroperoxides in Streptomyces coelicolor.
  J Bacteriol, 189, 6284-6292.  
16529980 D.W.Ellison, and V.L.Miller (2006).
Regulation of virulence by members of the MarR/SlyA family.
  Curr Opin Microbiol, 9, 153-159.  
16796676 E.H.Lee, S.A.Hill, R.Napier, and W.M.Shafer (2006).
Integration Host Factor is required for FarR repression of the farAB-encoded efflux pump of Neisseria gonorrhoeae.
  Mol Microbiol, 60, 1381-1400.  
16862595 K.H.Chin, Z.L.Tu, J.N.Li, C.C.Chou, A.H.Wang, and S.H.Chou (2006).
The crystal structure of XC1739: a putative multiple antibiotic-resistance repressor (MarR) from Xanthomonas campestris at 1.8 A resolution.
  Proteins, 65, 239-242.
PDB code: 2fa5
16980961 P.R.Chen, T.Bae, W.A.Williams, E.M.Duguid, P.A.Rice, O.Schneewind, and C.He (2006).
An oxidation-sensing mechanism is used by the global regulator MgrA in Staphylococcus aureus.
  Nat Chem Biol, 2, 591-595.
PDB code: 2bv6
16452421 W.Panmanee, P.Vattanaviboon, L.B.Poole, and S.Mongkolsuk (2006).
Novel organic hydroperoxide-sensing and responding mechanisms for OhrR, a major bacterial sensor and regulator of organic hydroperoxide stress.
  J Bacteriol, 188, 1389-1395.  
17028276 Y.Morita, L.Cao, V.C.Gould, M.B.Avison, and K.Poole (2006).
nalD encodes a second repressor of the mexAB-oprM multidrug efflux operon of Pseudomonas aeruginosa.
  J Bacteriol, 188, 8649-8654.  
16209951 M.Hong, M.Fuangthong, J.D.Helmann, and R.G.Brennan (2005).
Structure of an OhrR-ohrA operator complex reveals the DNA binding mechanism of the MarR family.
  Mol Cell, 20, 131-141.
PDB codes: 1z91 1z9c
15716455 M.K.Safo, Q.Zhao, T.P.Ko, F.N.Musayev, H.Robinson, N.Scarsdale, A.H.Wang, and G.L.Archer (2005).
Crystal structures of the BlaI repressor from Staphylococcus aureus and its complex with DNA: insights into transcriptional regulation of the bla and mec operons.
  J Bacteriol, 187, 1833-1844.
PDB codes: 1sd4 1sd6 1sd7 1xsd
15647287 R.S.De Silva, G.Kovacikova, W.Lin, R.K.Taylor, K.Skorupski, and F.J.Kull (2005).
Crystal structure of the virulence gene activator AphA from Vibrio cholerae reveals it is a novel member of the winged helix transcription factor superfamily.
  J Biol Chem, 280, 13779-13783.
PDB code: 1yg2
  16511135 Z.L.Tu, J.N.Li, K.H.Chin, C.C.Chou, C.C.Lee, H.L.Shr, P.C.Lyu, F.P.Gao, A.H.Wang, and S.H.Chou (2005).
Cloning, expression, crystallization and preliminary X-ray analysis of a putative multiple antibiotic resistance repressor protein (MarR) from Xanthomonas campestris.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 706-708.  
15105137 C.Llanes, D.Hocquet, C.Vogne, D.Benali-Baitich, C.Neuwirth, and P.Plésiat (2004).
Clinical strains of Pseudomonas aeruginosa overproducing MexAB-OprM and MexXY efflux pumps simultaneously.
  Antimicrob Agents Chemother, 48, 1797-1802.  
15353566 D.Tropel, and J.R.van der Meer (2004).
Bacterial transcriptional regulators for degradation pathways of aromatic compounds.
  Microbiol Mol Biol Rev, 68, 474-500.  
15225309 G.Kovacikova, W.Lin, and K.Skorupski (2004).
Vibrio cholerae AphA uses a novel mechanism for virulence gene activation that involves interaction with the LysR-type regulator AphB at the tcpPH promoter.
  Mol Microbiol, 53, 129-142.  
15047536 H.Maseda, I.Sawada, K.Saito, H.Uchiyama, T.Nakae, and N.Nomura (2004).
Enhancement of the mexAB-oprM efflux pump expression by a quorum-sensing autoinducer and its cancellation by a regulator, MexT, of the mexEF-oprN efflux pump operon in Pseudomonas aeruginosa.
  Antimicrob Agents Chemother, 48, 1320-1328.  
15387820 L.Cao, R.Srikumar, and K.Poole (2004).
MexAB-OprM hyperexpression in NalC-type multidrug-resistant Pseudomonas aeruginosa: identification and characterization of the nalC gene encoding a repressor of PA3720-PA3719.
  Mol Microbiol, 53, 1423-1436.  
  15374664 M.A.Prieto, B.Galán, B.Torres, A.Ferrández, C.Fernández, B.Miñambres, J.L.García, and E.Díaz (2004).
Aromatic metabolism versus carbon availability: the regulatory network that controls catabolism of less-preferred carbon sources in Escherichia coli.
  FEMS Microbiol Rev, 28, 503-518.  
14602920 B.Galán, A.Kolb, J.M.Sanz, J.L.García, and M.A.Prieto (2003).
Molecular determinants of the hpa regulatory system of Escherichia coli: the HpaR repressor.
  Nucleic Acids Res, 31, 6598-6609.  
14645274 E.H.Lee, C.Rouquette-Loughlin, J.P.Folster, and W.M.Shafer (2003).
FarR regulates the farAB-encoded efflux pump of Neisseria gonorrhoeae via an MtrR regulatory mechanism.
  J Bacteriol, 185, 7145-7152.  
14572535 I.T.Paulsen (2003).
Multidrug efflux pumps and resistance: regulation and evolution.
  Curr Opin Microbiol, 6, 446-451.  
14526032 K.Saito, H.Akama, E.Yoshihara, and T.Nakae (2003).
Mutations affecting DNA-binding activity of the MexR repressor of mexR-mexA-mexB-oprM operon expression.
  J Bacteriol, 185, 6195-6198.  
12649270 R.Y.Wu, R.G.Zhang, O.Zagnitko, I.Dementieva, N.Maltzev, J.D.Watson, R.Laskowski, P.Gornicki, and A.Joachimiak (2003).
Crystal structure of Enterococcus faecalis SlyA-like transcriptional factor.
  J Biol Chem, 278, 20240-20244.
PDB code: 1lj9
12456787 S.Grkovic, M.H.Brown, and R.A.Skurray (2002).
Regulation of bacterial drug export systems.
  Microbiol Mol Biol Rev, 66, 671.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.