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PDBsum entry 1t5e

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protein ligands Protein-protein interface(s) links
Transport protein PDB id
1t5e
Jmol
Contents
Protein chains
(+ 7 more) 231 a.a. *
Ligands
3GR ×9
GOL ×4
* Residue conservation analysis
PDB id:
1t5e
Name: Transport protein
Title: The structure of mexa
Structure: Multidrug resistance protein mexa. Chain: a, b, c, d, e, f, g, h, i, j, k, l, m. Engineered: yes
Source: Pseudomonas aeruginosa. Organism_taxid: 287. Gene: mexa, pa0425. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Heptamer (from PQS)
Resolution:
3.00Å     R-factor:   0.273     R-free:   0.285
Authors: M.K.Higgins,E.Bokma,E.Koronakis,C.Hughes,V.Koronakis
Key ref:
M.K.Higgins et al. (2004). Structure of the periplasmic component of a bacterial drug efflux pump. Proc Natl Acad Sci U S A, 101, 9994-9999. PubMed id: 15226509 DOI: 10.1073/pnas.0400375101
Date:
04-May-04     Release date:   18-May-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P52477  (MEXA_PSEAE) -  Multidrug resistance protein MexA
Seq:
Struc:
383 a.a.
231 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   2 terms 
  Biological process     transport   4 terms 
  Biochemical function     drug transmembrane transporter activity     1 term  

 

 
DOI no: 10.1073/pnas.0400375101 Proc Natl Acad Sci U S A 101:9994-9999 (2004)
PubMed id: 15226509  
 
 
Structure of the periplasmic component of a bacterial drug efflux pump.
M.K.Higgins, E.Bokma, E.Koronakis, C.Hughes, V.Koronakis.
 
  ABSTRACT  
 
Multidrug resistance among Gram-negative bacteria is conferred by three-component membrane pumps that expel diverse antibiotics from the cell. These efflux pumps consist of an inner membrane transporter such as the AcrB proton antiporter, an outer membrane exit duct of the TolC family, and a periplasmic protein known as the adaptor. We present the x-ray structure of the MexA adaptor from the human pathogen Pseudomonas aeruginosa. The elongated molecule contains three linearly arranged subdomains; a 47-A-long alpha-helical hairpin, a lipoyl domain, and a six-stranded beta-barrel. In the crystal, hairpins of neighboring MexA monomers pack side-by-side to form twisted arcs. We discuss the implications of the packing of molecules within the crystal. On the basis of the structure and packing, we suggest a model for the key periplasmic interaction between the outer membrane channel and the adaptor protein in the assembled drug efflux pump.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Crystallographic interactions between neighboring MexA molecules are mediated by conserved residues down the exposed surfaces of the MexA hairpin. (a) An alignment of the hairpin regions of eight drug efflux adaptors, adapted from Johnson and Church (13). Residues lying in the a and d positions of the hairpin are highlighted in yellow. Small residues on the exposed surfaces in position c and f of the hairpin are light green, with dark green indicating large hydrogen-bonding residues at the ends of these exposed surfaces. PA, P. aeruginosa; HY, Helicobacter pylori; EC, E. coli. The residue numbers are for mature proteins, after removal of the periplasmic signal sequences. (b) Three views of a surface representation of the MexA monomer. Small conserved residues are again colored light green whereas the larger hydrogen-bonding residues at either end of the conserved region are dark green.
Figure 3.
Fig. 3. The arrangement of MexA molecules within the crystal. (a)C traces of the 13 molecules in the asymmetric unit are shown as lines with each molecule a different color. This complex cylinder is formed from two arcs of 6 or 7 molecules. (b) The C trace of the lower arc of 6 MexA molecules viewed from the top and side.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20981744 C.C.Su, F.Long, and E.W.Yu (2011).
The Cus efflux system removes toxic ions via a methionine shuttle.
  Protein Sci, 20, 6.  
21350490 C.C.Su, F.Long, M.T.Zimmermann, K.R.Rajashankar, R.L.Jernigan, and E.W.Yu (2011).
Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli.
  Nature, 470, 558-562.
PDB code: 3ne5
21245342 X.Y.Pei, P.Hinchliffe, M.F.Symmons, E.Koronakis, R.Benz, C.Hughes, and V.Koronakis (2011).
Structures of sequential open states in a symmetrical opening transition of the TolC exit duct.
  Proc Natl Acad Sci U S A, 108, 2112-2117.
PDB codes: 2wmz 2xmn
20583998 A.Welch, C.U.Awah, S.Jing, H.W.van Veen, and H.Venter (2010).
Promiscuous partnering and independent activity of MexB, the multidrug transporter protein from Pseudomonas aeruginosa.
  Biochem J, 430, 355-364.  
  20379386 A.Y.Xiao, J.Wang, and M.H.Saier (2010).
Bacterial Adaptor Membrane Fusion Proteins and the Structurally Dissimilar Outer Membrane Auxiliary Proteins Have Exchanged Central Domains in alpha-Proteobacteria.
  Int J Microbiol, 2010, 589391.  
20038628 C.A.Elkins, L.B.Mullis, D.W.Lacher, and C.M.Jung (2010).
Single nucleotide polymorphism analysis of the major tripartite multidrug efflux pump of Escherichia coli: functional conservation in disparate animal reservoirs despite exposure to antimicrobial chemotherapy.
  Antimicrob Agents Chemother, 54, 1007-1015.  
20525265 E.Perrin, M.Fondi, M.C.Papaleo, I.Maida, S.Buroni, M.R.Pasca, G.Riccardi, and R.Fani (2010).
Exploring the HME and HAE1 efflux systems in the genus Burkholderia.
  BMC Evol Biol, 10, 164.  
20534468 F.De Angelis, J.K.Lee, J.D.O'Connell, L.J.Miercke, K.H.Verschueren, V.Srinivasan, C.Bauvois, C.Govaerts, R.A.Robbins, J.M.Ruysschaert, R.M.Stroud, and G.Vandenbussche (2010).
Metal-induced conformational changes in ZneB suggest an active role of membrane fusion proteins in efflux resistance systems.
  Proc Natl Acad Sci U S A, 107, 11038-11043.
PDB code: 3lnn
20865003 F.Long, C.C.Su, M.T.Zimmermann, S.E.Boyken, K.R.Rajashankar, R.L.Jernigan, and E.W.Yu (2010).
Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport.
  Nature, 467, 484-488.
PDB codes: 3k07 3kso 3kss
20399187 G.Phan, H.Benabdelhak, M.B.Lascombe, P.Benas, S.Rety, M.Picard, A.Ducruix, C.Etchebest, and I.Broutin (2010).
Structural and dynamical insights into the opening mechanism of P. aeruginosa OprM channel.
  Structure, 18, 507-517.
PDB code: 3d5k
20581201 H.M.Kim, Y.Xu, M.Lee, S.Piao, S.H.Sim, N.C.Ha, and K.Lee (2010).
Functional relationships between the AcrA hairpin tip region and the TolC aperture tip region for the formation of the bacterial tripartite efflux pump AcrAB-TolC.
  J Bacteriol, 192, 4498-4503.  
19695261 C.C.Su, F.Yang, F.Long, D.Reyon, M.D.Routh, D.W.Kuo, A.K.Mokhtari, J.D.Van Ornam, K.L.Rabe, J.A.Hoy, Y.J.Lee, K.R.Rajashankar, and E.W.Yu (2009).
Crystal structure of the membrane fusion protein CusB from Escherichia coli.
  J Mol Biol, 393, 342-355.
PDB codes: 3h94 3h9i 3h9t 3ooc 3opo 3ow7
19805313 E.B.Tikhonova, V.Dastidar, V.V.Rybenkov, and H.I.Zgurskaya (2009).
Kinetic control of TolC recruitment by multidrug efflux complexes.
  Proc Natl Acad Sci U S A, 106, 16416-16421.  
19026770 H.Nikaido, and Y.Takatsuka (2009).
Mechanisms of RND multidrug efflux pumps.
  Biochim Biophys Acta, 1794, 769-781.  
19231985 H.Nikaido (2009).
Multidrug resistance in bacteria.
  Annu Rev Biochem, 78, 119-146.  
19602147 J.Scherer, and D.H.Nies (2009).
CzcP is a novel efflux system contributing to transition metal resistance in Cupriavidus metallidurans CH34.
  Mol Microbiol, 73, 601-621.  
19129185 K.Larue, M.S.Kimber, R.Ford, and C.Whitfield (2009).
Biochemical and structural analysis of bacterial O-antigen chain length regulator proteins reveals a conserved quaternary structure.
  J Biol Chem, 284, 7395-7403.  
  19416927 K.M.Pos (2009).
Trinity revealed: Stoichiometric complex assembly of a bacterial multidrug efflux pump.
  Proc Natl Acad Sci U S A, 106, 6893-6894.  
19258536 L.Cuthbertson, I.L.Mainprize, J.H.Naismith, and C.Whitfield (2009).
Pivotal roles of the outer membrane polysaccharide export and polysaccharide copolymerase protein families in export of extracellular polysaccharides in gram-negative bacteria.
  Microbiol Mol Biol Rev, 73, 155-177.  
  19342493 M.F.Symmons, E.Bokma, E.Koronakis, C.Hughes, and V.Koronakis (2009).
The assembled structure of a complete tripartite bacterial multidrug efflux pump.
  Proc Natl Acad Sci U S A, 106, 7173-7178.
PDB code: 2v4d
19337368 M.Reffay, Y.Gambin, H.Benabdelhak, G.Phan, N.Taulier, A.Ducruix, R.S.Hodges, and W.Urbach (2009).
Tracking membrane protein association in model membranes.
  PLoS ONE, 4, e5035.  
19411330 Q.Ge, Y.Yamada, and H.Zgurskaya (2009).
The C-terminal domain of AcrA is essential for the assembly and function of the multidrug efflux pump AcrAB-TolC.
  J Bacteriol, 191, 4365-4371.  
19289182 R.Misra, and V.N.Bavro (2009).
Assembly and transport mechanism of tripartite drug efflux systems.
  Biochim Biophys Acta, 1794, 817-825.  
19761586 S.Buroni, M.R.Pasca, R.S.Flannagan, S.Bazzini, A.Milano, I.Bertani, V.Venturi, M.A.Valvano, and G.Riccardi (2009).
Assessment of three Resistance-Nodulation-Cell Division drug efflux transporters of Burkholderia cenocepacia in intrinsic antibiotic resistance.
  BMC Microbiol, 9, 200.  
19713238 T.Mima, N.Kohira, Y.Li, H.Sekiya, W.Ogawa, T.Kuroda, and T.Tsuchiya (2009).
Gene cloning and characteristics of the RND-type multidrug efflux pump MuxABC-OpmB possessing two RND components in Pseudomonas aeruginosa.
  Microbiology, 155, 3509-3517.  
18830684 T.von Rozycki, and D.H.Nies (2009).
Cupriavidus metallidurans: evolution of a metal-resistant bacterium.
  Antonie Van Leeuwenhoek, 96, 115-139.  
19678712 X.Z.Li, and H.Nikaido (2009).
Efflux-mediated drug resistance in bacteria: an update.
  Drugs, 69, 1555-1623.  
18535149 A.L.Davidson, E.Dassa, C.Orelle, and J.Chen (2008).
Structure, function, and evolution of bacterial ATP-binding cassette systems.
  Microbiol Mol Biol Rev, 72, 317.  
18024521 G.Krishnamoorthy, E.B.Tikhonova, and H.I.Zgurskaya (2008).
Fitting periplasmic membrane fusion proteins to inner membrane transporters: mutations that enable Escherichia coli AcrA to function with Pseudomonas aeruginosa MexB.
  J Bacteriol, 190, 691-698.  
18389081 I.Bunikis, K.Denker, Y.Ostberg, C.Andersen, R.Benz, and S.Bergström (2008).
An RND-type efflux system in Borrelia burgdorferi is involved in virulence and resistance to antimicrobial compounds.
  PLoS Pathog, 4, e1000009.  
18186471 M.M.Vanini, A.Spisni, M.L.Sforça, T.A.Pertinhez, and C.E.Benedetti (2008).
The solution structure of the outer membrane lipoprotein OmlA from Xanthomonas axonopodis pv. citri reveals a protein fold implicated in protein-protein interaction.
  Proteins, 71, 2051-2064.
PDB code: 2pxg
18676884 M.Sugimura, H.Maseda, H.Hanaki, and T.Nakae (2008).
Macrolide antibiotic-mediated downregulation of MexAB-OprM efflux pump expression in Pseudomonas aeruginosa.
  Antimicrob Agents Chemother, 52, 4141-4144.  
  18453709 S.Piao, Y.Xu, and N.C.Ha (2008).
Crystallization and preliminary X-ray crystallographic analysis of MacA from Actinobacillus actinomycetemcomitans.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 391-393.  
18485072 T.Gristwood, P.C.Fineran, L.Everson, and G.P.Salmond (2008).
PigZ, a TetR/AcrR family repressor, modulates secondary metabolism via the expression of a putative four-component resistance-nodulation-cell-division efflux pump, ZrpADBC, in Serratia sp. ATCC 39006.
  Mol Microbiol, 69, 418-435.  
18406332 V.N.Bavro, Z.Pietras, N.Furnham, L.Pérez-Cano, J.Fernández-Recio, X.Y.Pei, R.Misra, and B.Luisi (2008).
Assembly and channel opening in a bacterial drug efflux machine.
  Mol Cell, 30, 114-121.
PDB codes: 2vdd 2vde
17275331 D.Das, Q.S.Xu, J.Y.Lee, I.Ankoudinova, C.Huang, Y.Lou, A.DeGiovanni, R.Kim, and S.H.Kim (2007).
Crystal structure of the multidrug efflux transporter AcrB at 3.1A resolution reveals the N-terminal region with conserved amino acids.
  J Struct Biol, 158, 494-502.
PDB code: 2i6w
17586626 D.Nehme, and K.Poole (2007).
Assembly of the MexAB-OprM multidrug pump of Pseudomonas aeruginosa: component interactions defined by the study of pump mutant suppressors.
  J Bacteriol, 189, 6118-6127.  
17214741 E.B.Tikhonova, V.K.Devroy, S.Y.Lau, and H.I.Zgurskaya (2007).
Reconstitution of the Escherichia coli macrolide transporter: the periplasmic membrane fusion protein MacA stimulates the ATPase activity of MacB.
  Mol Microbiol, 63, 895-910.  
17159924 O.Lomovskaya, H.I.Zgurskaya, M.Totrov, and W.J.Watkins (2007).
Waltzing transporters and 'the dance macabre' between humans and bacteria.
  Nat Rev Drug Discov, 6, 56-65.  
17360572 S.Lobedanz, E.Bokma, M.F.Symmons, E.Koronakis, C.Hughes, and V.Koronakis (2007).
A periplasmic coiled-coil interface underlying TolC recruitment and the assembly of bacterial drug efflux pumps.
  Proc Natl Acad Sci U S A, 104, 4612-4617.  
18073115 S.Törnroth-Horsefield, P.Gourdon, R.Horsefield, L.Brive, N.Yamamoto, H.Mori, A.Snijder, and R.Neutze (2007).
Crystal structure of AcrB in complex with a single transmembrane subunit reveals another twist.
  Structure, 15, 1663-1673.
PDB code: 2rdd
17665187 S.Trépout, J.C.Taveau, S.Mornet, H.Benabdelhak, A.Ducruix, and O.Lambert (2007).
Organization of reconstituted lipoprotein MexA onto supported lipid membrane.
  Eur Biophys J, 36, 1029-1037.  
16707668 G.Vediyappan, T.Borisova, and J.A.Fralick (2006).
Isolation and characterization of VceC gain-of-function mutants that can function with the AcrAB multiple-drug-resistant efflux pump of Escherichia coli.
  J Bacteriol, 188, 3757-3762.  
16717405 H.Yoneyama, and R.Katsumata (2006).
Antibiotic resistance in bacteria and its future for novel antibiotic development.
  Biosci Biotechnol Biochem, 70, 1060-1075.  
16635801 J.J.Barker (2006).
Antibacterial drug discovery and structure-based design.
  Drug Discov Today, 11, 391-404.  
16531241 J.Mikolosko, K.Bobyk, H.I.Zgurskaya, and P.Ghosh (2006).
Conformational flexibility in the multidrug efflux system protein AcrA.
  Structure, 14, 577-587.
PDB code: 2f1m
16614254 L.J.Piddock (2006).
Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria.
  Clin Microbiol Rev, 19, 382-402.  
16648168 L.Vaccaro, V.Koronakis, and M.S.Sansom (2006).
Flexibility in a drug transport accessory protein: molecular dynamics simulations of MexA.
  Biophys J, 91, 558-564.  
17546510 M.H.Saier (2006).
Protein secretion and membrane insertion systems in gram-negative bacteria.
  J Membr Biol, 214, 75-90.  
16499616 M.Iwashita, J.Nishi, N.Wakimoto, R.Fujiyama, K.Yamamoto, K.Tokuda, K.Manago, and Y.Kawano (2006).
Role of the carboxy-terminal region of the outer membrane protein AatA in the export of dispersin from enteroaggregative Escherichia coli.
  FEMS Microbiol Lett, 256, 266-272.  
16619027 M.Kowarik, N.M.Young, S.Numao, B.L.Schulz, I.Hug, N.Callewaert, D.C.Mills, D.C.Watson, M.Hernandez, J.F.Kelly, M.Wacker, and M.Aebi (2006).
Definition of the bacterial N-glycosylation site consensus sequence.
  EMBO J, 25, 1957-1966.  
17009943 P.Grossi, and D.Dalla Gasperina (2006).
Treatment of Pseudomonas aeruginosa infection in critically ill patients.
  Expert Rev Anti Infect Ther, 4, 639-662.  
16857052 P.Guglierame, M.R.Pasca, E.De Rossi, S.Buroni, P.Arrigo, G.Manina, and G.Riccardi (2006).
Efflux pump genes of the resistance-nodulation-division family in Burkholderia cenocepacia genome.
  BMC Microbiol, 6, 66.  
16451186 S.Eda, H.Maseda, E.Yoshihara, and T.Nakae (2006).
Assignment of the outer-membrane-subunit-selective domain of the membrane fusion protein in the tripartite xenobiotic efflux pump of Pseudomonas aeruginosa.
  FEMS Microbiol Lett, 254, 101-107.  
16915237 S.Murakami, R.Nakashima, E.Yamashita, T.Matsumoto, and A.Yamaguchi (2006).
Crystal structures of a multidrug transporter reveal a functionally rotating mechanism.
  Nature, 443, 173-179.
PDB codes: 2dhh 2dr6 2drd
16237030 A.L.Pimenta, K.Racher, L.Jamieson, M.A.Blight, and I.B.Holland (2005).
Mutations in HlyD, part of the type 1 translocator for hemolysin secretion, affect the folding of the secreted toxin.
  J Bacteriol, 187, 7471-7480.  
16166532 C.Bleuel, C.Grosse, N.Taudte, J.Scherer, D.Wesenberg, G.J.Krauss, D.H.Nies, and G.Grass (2005).
TolC is involved in enterobactin efflux across the outer membrane of Escherichia coli.
  J Bacteriol, 187, 6701-6707.  
16189126 D.Nehme, and K.Poole (2005).
Interaction of the MexA and MexB components of the MexAB-OprM multidrug efflux system of Pseudomonas aeruginosa: identification of MexA extragenic suppressors of a T578I mutation in MexB.
  Antimicrob Agents Chemother, 49, 4375-4378.  
16166543 E.W.Yu, J.R.Aires, G.McDermott, and H.Nikaido (2005).
A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study.
  J Bacteriol, 187, 6804-6815.
PDB codes: 1t9t 1t9u 1t9v 1t9w 1t9x 1t9y
16158236 G.Grass, B.Fricke, and D.H.Nies (2005).
Control of expression of a periplasmic nickel efflux pump by periplasmic nickel concentrations.
  Biometals, 18, 437-448.  
  16508113 H.Akama, M.Kanemaki, T.Tsukihara, A.Nakagawa, and T.Nakae (2005).
Preliminary crystallographic analysis of the antibiotic discharge outer membrane lipoprotein OprM of Pseudomonas aeruginosa with an exceptionally long unit cell and complex lattice structure.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 131-133.  
15996519 J.M.Pagès, M.Masi, and J.Barbe (2005).
Inhibitors of efflux pumps in Gram-negative bacteria.
  Trends Mol Med, 11, 382-389.  
15743938 J.R.Aires, and H.Nikaido (2005).
Aminoglycosides are captured from both periplasm and cytoplasm by the AcrD multidrug efflux transporter of Escherichia coli.
  J Bacteriol, 187, 1923-1929.  
15901719 M.Masi, J.M.Pagès, C.Villard, and E.Pradel (2005).
The eefABC multidrug efflux pump operon is repressed by H-NS in Enterobacter aerogenes.
  J Bacteriol, 187, 3894-3897.  
15743933 O.Lomovskaya, and M.Totrov (2005).
Vacuuming the periplasm.
  J Bacteriol, 187, 1879-1883.  
15855547 R.Chuanchuen, T.Murata, N.Gotoh, and H.P.Schweizer (2005).
Substrate-dependent utilization of OprM or OpmH by the Pseudomonas aeruginosa MexJK efflux pump.
  Antimicrob Agents Chemother, 49, 2133-2136.  
16133099 S.Silver, and l.e. .T.Phung (2005).
A bacterial view of the periodic table: genes and proteins for toxic inorganic ions.
  J Ind Microbiol Biotechnol, 32, 587-605.  
15547276 D.Munkelt, G.Grass, and D.H.Nies (2004).
The chromosomally encoded cation diffusion facilitator proteins DmeF and FieF from Wautersia metallidurans CH34 are transporters of broad metal specificity.
  J Bacteriol, 186, 8036-8043.  
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.