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* Residue conservation analysis
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PDB id:
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Transport protein
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Title:
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Conformational flexibility in the multidrug efflux system protein acra
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Structure:
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Acriflavine resistance protein a. Chain: a, b, c, d. Fragment: residues 45-312. Engineered: yes. Mutation: yes
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Source:
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Escherichia coli. Organism_taxid: 562. Strain: jm109. Gene: acra, lir, mtca. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Biol. unit:
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Dimer (from
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Resolution:
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2.71Å
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R-factor:
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0.239
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R-free:
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0.275
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Authors:
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J.Mikolosko,K.Bobyk,H.I.Zgurskaya,P.Ghosh
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Key ref:
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J.Mikolosko
et al.
(2006).
Conformational flexibility in the multidrug efflux system protein AcrA.
Structure,
14,
577-587.
PubMed id:
DOI:
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Date:
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14-Nov-05
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Release date:
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21-Mar-06
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PROCHECK
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Headers
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References
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DOI no:
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Structure
14:577-587
(2006)
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PubMed id:
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Conformational flexibility in the multidrug efflux system protein AcrA.
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J.Mikolosko,
K.Bobyk,
H.I.Zgurskaya,
P.Ghosh.
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ABSTRACT
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Intrinsic resistance to multiple drugs in many gram-negative bacterial pathogens
is conferred by resistance nodulation cell division efflux pumps, which are
composed of three essential components as typified by the extensively
characterized Escherichia coli AcrA-AcrB-TolC system. The inner membrane
drug:proton antiporter AcrB and the outer membrane channel TolC export
chemically diverse compounds out of the bacterial cell, and require the activity
of the third component, the periplasmic protein AcrA. The crystal structures of
AcrB and TolC have previously been determined, and we complete the molecular
picture of the efflux system by presenting the structure of a stable fragment of
AcrA. The AcrA fragment resembles the elongated sickle shape of its homolog
Pseudomonas aeruginosa MexA, being composed of three domains: beta-barrel,
lipoyl, and alpha-helical hairpin. Notably, unsuspected conformational
flexibility in the alpha-helical hairpin domain of AcrA is observed, which has
potential mechanistic significance in coupling between AcrA conformations and
TolC channel opening.
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Selected figure(s)
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Figure 6.
Figure 6. Comparison of the TolC and AcrA(45-312)-4M
Coiled-Coils
The magnitude of conformational change
predicted for the opening of the TolC channel coincides with the
flexibility observed in the AcrA a-helical hairpin domain. The
inner (yellow) and outer helices (blue) of TolC are shown
superposed based on the internal structural repeat (residues
16-98 and 222-316). Below these are molecules B (red) and C
(green) of AcrA(45-312)-4M, as superposed on the lipoyl domain.
Direct engagement of AcrA and TolC is not modeled.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2006,
14,
577-587)
copyright 2006.
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Figure was
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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C.C.Su,
F.Long,
and
E.W.Yu
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The Cus efflux system removes toxic ions via a methionine shuttle.
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Protein Sci,
20,
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C.C.Su,
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K.R.Rajashankar,
R.L.Jernigan,
and
E.W.Yu
(2011).
Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli.
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Nature,
470,
558-562.
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PDB code:
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|
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|
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C.Oswald,
and
K.M.Pos
(2011).
Drug resistance: a periplasmic ménage à trois.
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Chem Biol,
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E.B.Tikhonova,
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and
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(2011).
Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC.
|
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Chem Biol,
18,
454-463.
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R.Kulathila,
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and
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(2011).
Crystal Structure of Escherichia coli CusC, the Outer Membrane Component of a Heavy Metal Efflux Pump.
|
| |
PLoS One,
6,
e15610.
|
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PDB code:
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R.Nakashima,
K.Sakurai,
S.Yamasaki,
K.Nishino,
and
A.Yamaguchi
(2011).
Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket.
|
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Nature,
480,
565-569.
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PDB codes:
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T.K.Janganan,
L.Zhang,
V.N.Bavro,
D.Matak-Vinkovic,
N.P.Barrera,
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P.G.Steel,
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M.I.Borges-Walmsley,
and
A.R.Walmsley
(2011).
Opening of the outer membrane protein channel in tripartite efflux pumps is induced by interaction with the membrane fusion partner.
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J Biol Chem,
286,
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A.Welch,
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and
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(2010).
Promiscuous partnering and independent activity of MexB, the multidrug transporter protein from Pseudomonas aeruginosa.
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Biochem J,
430,
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A.Y.Xiao,
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Bacterial Adaptor Membrane Fusion Proteins and the Structurally Dissimilar Outer Membrane Auxiliary Proteins Have Exchanged Central Domains in alpha-Proteobacteria.
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Int J Microbiol,
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E.H.Kim,
C.Rensing,
and
M.M.McEvoy
(2010).
Chaperone-mediated copper handling in the periplasm.
|
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Nat Prod Rep,
27,
711-719.
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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.
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Proc Natl Acad Sci U S A,
107,
11038-11043.
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PDB code:
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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.
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Nature,
467,
484-488.
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PDB codes:
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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.
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Structure,
18,
507-517.
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PDB code:
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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.
|
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|
|
|
|
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H.S.Kim,
D.Nagore,
and
H.Nikaido
(2010).
Multidrug efflux pump MdtBC of Escherichia coli is active only as a B2C heterotrimer.
|
| |
J Bacteriol,
192,
1377-1386.
|
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J.A.Bohnert,
B.Karamian,
and
H.Nikaido
(2010).
Optimized Nile Red efflux assay of AcrAB-TolC multidrug efflux system shows competition between substrates.
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Antimicrob Agents Chemother,
54,
3770-3775.
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J.W.Weeks,
T.Celaya-Kolb,
S.Pecora,
and
R.Misra
(2010).
AcrA suppressor alterations reverse the drug hypersensitivity phenotype of a TolC mutant by inducing TolC aperture opening.
|
| |
Mol Microbiol,
75,
1468-1483.
|
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|
|
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R.Schulz,
A.V.Vargiu,
F.Collu,
U.Kleinekathöfer,
and
P.Ruggerone
(2010).
Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
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PLoS Comput Biol,
6,
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|
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|
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|
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X.Q.Yao,
H.Kenzaki,
S.Murakami,
and
S.Takada
(2010).
Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations.
|
| |
Nat Commun,
1,
117.
|
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|
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|
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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.
|
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PDB codes:
|
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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.
|
|
|
|
|
|
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H.Nikaido,
and
Y.Takatsuka
(2009).
Mechanisms of RND multidrug efflux pumps.
|
| |
Biochim Biophys Acta,
1794,
769-781.
|
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|
H.Nikaido
(2009).
Multidrug resistance in bacteria.
|
| |
Annu Rev Biochem,
78,
119-146.
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|
|
H.T.Lin,
V.N.Bavro,
N.P.Barrera,
H.M.Frankish,
S.Velamakanni,
H.W.van Veen,
C.V.Robinson,
M.I.Borges-Walmsley,
and
A.R.Walmsley
(2009).
MacB ABC Transporter Is a Dimer Whose ATPase Activity and Macrolide-binding Capacity Are Regulated by the Membrane Fusion Protein MacA.
|
| |
J Biol Chem,
284,
1145-1154.
|
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|
|
|
|
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J.L.Rosner,
and
R.G.Martin
(2009).
An excretory function for the Escherichia coli outer membrane pore TolC: upregulation of marA and soxS transcription and Rob activity due to metabolites accumulated in tolC mutants.
|
| |
J Bacteriol,
191,
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|
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J.M.Blair,
R.M.La Ragione,
M.J.Woodward,
and
L.J.Piddock
(2009).
Periplasmic adaptor protein AcrA has a distinct role in the antibiotic resistance and virulence of Salmonella enterica serovar Typhimurium.
|
| |
J Antimicrob Chemother,
64,
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M.S.Kimber,
R.Ford,
and
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(2009).
Biochemical and Structural Analysis of Bacterial O-antigen Chain Length Regulator Proteins Reveals a Conserved Quaternary Structure.
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and
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Pivotal roles of the outer membrane polysaccharide export and polysaccharide copolymerase protein families in export of extracellular polysaccharides in gram-negative bacteria.
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Microbiol Mol Biol Rev,
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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.
|
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J Bacteriol,
191,
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R.Misra,
and
V.N.Bavro
(2009).
Assembly and transport mechanism of tripartite drug efflux systems.
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Biochim Biophys Acta,
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817-825.
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R.Schulz,
and
U.Kleinekathöfer
(2009).
Transitions between closed and open conformations of TolC: the effects of ions in simulations.
|
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Biophys J,
96,
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X.Z.Li,
and
H.Nikaido
(2009).
Efflux-mediated drug resistance in bacteria: an update.
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Drugs,
69,
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F.E.Jacobsen,
and
D.P.Giedroc
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Coordination chemistry of bacterial metal transport and sensing.
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Chem Rev,
109,
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G.Krishnamoorthy,
E.B.Tikhonova,
and
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(2008).
Fitting periplasmic membrane fusion proteins to inner membrane transporters: mutations that enable Escherichia coli AcrA to function with Pseudomonas aeruginosa MexB.
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| |
J Bacteriol,
190,
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L.Vaccaro,
K.A.Scott,
and
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Gating at both ends and breathing in the middle: conformational dynamics of TolC.
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Biophys J,
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F.Verrey,
K.Diederichs,
and
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Engineered disulfide bonds support the functional rotation mechanism of multidrug efflux pump AcrB.
|
| |
Nat Struct Mol Biol,
15,
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S.Piao,
Y.Xu,
and
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Crystallization and preliminary X-ray crystallographic analysis of MacA from Actinobacillus actinomycetemcomitans.
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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.
|
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Mol Microbiol,
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Assembly and channel opening in a bacterial drug efflux machine.
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Q.S.Xu,
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K.Diederichs,
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(2006).
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|
| |
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313,
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PDB codes:
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T.Matsumoto,
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(2006).
Crystal structures of a multidrug transporter reveal a functionally rotating mechanism.
|
| |
Nature,
443,
173-179.
|
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PDB codes:
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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.
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Links
