RegulonDB RegulonDB 11.1: Gene Form
   

acrB gene in Escherichia coli K-12 genome


Gene local context to scale (view description)

acrB acrA tomB BasR PdhR CpxR terminator anti-terminator anti-anti-terminator acrBp acrBp TSS_622 TSS_622 TSS_621 TSS_621 TSS_620 TSS_620 TSS_619 TSS_619 TSS_618 TSS_618 TSS_617 TSS_617 TSS_616 TSS_616 tomBp tomBp hhap6 hhap6 TSS_615 (cluster) TSS_615 (cluster) TSS_614 TSS_614 TSS_613 TSS_613

Gene      
Name: acrB    Texpresso search in the literature
Synonym(s): ECK0456, EG11704, acrE, b0462
Genome position(nucleotides): 481254 <-- 484403
Strand: reverse
Sequence: Get nucleotide sequence FastaFormat
GC content %:  
 53.97
External database links:  
ASAP:
 ABE-0001601
ECHOBASE:
 EB1655
ECOLIHUB:
 acrB
OU-MICROARRAY:
 b0462
STRING:
 511145.b0462
COLOMBOS: acrB


Product      
Name: multidrug efflux pump RND permease AcrB
Synonym(s): AcrB, AcrB RND permease, AcrE, acriflavine resistance protein B
Sequence: Get amino acid sequence Fasta Format
Cellular location: inner membrane,periplasmic space
Molecular weight: 113.573
Isoelectric point: 5.232
Motif(s):
 
Type Positions Sequence Comment
1 -> 1030 MPNFFIDRPIFAWVIAIIIMLAGGLAILKLPVAQYPTIAPPAVTISASYPGADAKTVQDTVTQVIEQNMNGIDNLMYMSSNSDSTGTVQITLTFESGTDADIAQVQVQNKLQLAMPLLPQEVQQQGVSVEKSSSSFLMVVGVINTDGTMTQEDISDYVAANMKDAISRTSGVGDVQLFGSQYAMRIWMNPNELNKFQLTPVDVITAIKAQNAQVAAGQLGGTPPVKGQQLNASIIAQTRLTSTEEFGKILLKVNQDGSRVLLRDVAKIELGGENYDIIAEFNGQPASGLGIKLATGANALDTAAAIRAELAKMEPFFPSGLKIVYPYDTTPFVKISIHEVVKTLVEAIILVFLVMYLFLQNFRATLIPTIAVPVVLLGTFAVLAAFGFSINTLTMFGMVLAIGLLVDDAIVVVENVERVMAEEGLPPKEATRKSMGQIQGALVGIAMVLSAVFVPMAFFGGSTGAIYRQFSITIVSAMALSVLVALILTPALCATMLKPIAKGDHGEGKKGFFGWFNRMFEKSTHHYTDSVGGILRSTGRYLVLYLIIVVGMAYLFVRLPSSFLPDEDQGVFMTMVQLPAGATQERTQKVLNEVTHYYLTKEKNNVESVFAVNGFGFAGRGQNTGIAFVSLKDWADRPGEENKVEAITMRATRAFSQIKDAMVFAFNLPAIVELGTATGFDFELIDQAGLGHEKLTQARNQLLAEAAKHPDMLTSVRPNGLEDTPQFKIDIDQEKAQALGVSINDINTTLGAAWGGSYVNDFIDRGRVKKVYVMSEAKYRMLPDDIGDWYVRAADGQMVPFSAFSSSRWEYGSPRLERYNGLPSMEILGQAAPGKSTGEAMELMEQLASKLPTGVGYDWTGMSYQERLSGNQAPSLYAISLIVVFLCLAALYESWSIPFSVMLVVPLGVIGALLAATFRGLTNDVYFQVGLLTTIGLSAKNAILIVEFAKDLMDKEGKGLIEATLDAVRMRLRPILMTSLAFILGVMPLVISTGAGSGAQNAVGTGVMGGMVTATVLAIFFVPVFFVVVR
10 -> 28 IFAWVIAIIIMLAGGLAIL UniProt: Helical; Name=1.
288 -> 288 G G → D: strains expressing the mutant protein accumulate less ciprofloxacin but more doxorubicin and minocycline than strains expressing the wild type proteion
337 -> 356 IHEVVKTLVEAIILVFLVMY UniProt: Helical; Name=2.
366 -> 385 LIPTIAVPVVLLGTFAVLAA UniProt: Helical; Name=3.

 
Classification:
Multifun Terms (GenProtEC)  
  4 - transport --> 4.2 - Electrochemical potential driven transporters
  5 - cell processes --> 5.6 - protection --> 5.6.4 - drug resistance/sensitivity
  6 - cell structure --> 6.1 - membrane
Gene Ontology Terms (GO)  
cellular_component GO:0098567 - periplasmic side of plasma membrane
GO:0016020 - membrane
GO:0030288 - outer membrane-bounded periplasmic space
GO:0005886 - plasma membrane
GO:0005887 - integral component of plasma membrane
GO:0016021 - integral component of membrane
GO:1990281 - efflux pump complex
molecular_function GO:0015567 - alkane transmembrane transporter activity
GO:0015125 - bile acid transmembrane transporter activity
GO:0005515 - protein binding
GO:0015562 - efflux transmembrane transporter activity
GO:0022857 - transmembrane transporter activity
GO:0015299 - solute:proton antiporter activity
GO:0042802 - identical protein binding
GO:0042910 - xenobiotic transmembrane transporter activity
GO:0042931 - enterobactin transmembrane transporter activity
biological_process GO:0015895 - alkane transport
GO:0140330 - xenobiotic detoxification by transmembrane export across the cell outer membrane
GO:0009410 - response to xenobiotic stimulus
GO:0009636 - response to toxic substance
GO:0046677 - response to antibiotic
GO:0015908 - fatty acid transport
GO:0055085 - transmembrane transport
GO:0042930 - enterobactin transport
GO:0042908 - xenobiotic transport
GO:0015721 - bile acid and bile salt transport
Note(s): Note(s): ...[more].
Reference(s): [1] Ababou A. 2018
[2] Adler M., et al., 2016
[3] Alon Cudkowicz N., et al., 2019
[4] Aoki SK., et al., 2008
[5] Atzori A., et al., 2020
[6] Atzori A., et al., 2019
[7] Atzori A., et al., 2019
[8] Bohnert JA., et al., 2013
[9] Bohnert JA., et al., 2008
[10] Bohnert JA., et al., 2011
[11] Brandstatter L., et al., 2011
[12] Das D., et al., 2007
[13] Elkins CA., et al., 2003
[14] Fang J., et al., 2013
[15] Feng Z., et al., 2012
[16] Fischer N., et al., 2013
[17] Fisher MA., et al., 2014
[18] Glover CA., et al., 2011
[19] Grimsey EM., et al., 2020
[20] Hung LW., et al., 2013
[21] Husain F., et al., 2010
[22] Iyer R., et al., 2015
[23] Jahn LJ., et al., 2017
[24] Jewel Y., et al., 2017
[25] Jewel Y., et al., 2020
[26] Kinana AD., et al., 2016
[27] Kinana AD., et al., 2016
[28] Kobayashi N., et al., 2014
[29] Langevin AM., et al., 2018
[30] Liu M., et al., 2017
[31] Lu W., et al., 2012
[32] Lu W., et al., 2014
[33] Lu W., et al., 2011
[34] Lu W., et al., 2011
[35] Ly K., et al., 2014
[36] Malvacio I., et al., 2019
[37] Marshall RL., et al., 2020
[38] Mishima H., et al., 2015
[39] Mowla R., et al., 2018
[40] Muller RT., et al., 2017
[41] Murakami S., et al., 2004
[42] Nakashima R., et al., 2018
[43] Nikaido H. 2018
[44] Opperman TJ., et al., 2014
[45] Polyak SW., et al., 2020
[46] Pos KM., et al., 2004
[47] Ramaswamy VK., et al., 2017
[48] Reading E., et al., 2020
[49] Schmidt TH., et al., 2016
[50] Schuldiner S. 2018
[51] Schulz R., et al., 2010
[52] Schulz R., et al., 2011
[53] Schulz R., et al., 2015
[54] Schuster S., et al., 2016
[55] Simsir M., et al., 2021
[56] Sjuts H., et al., 2016
[57] Soparkar K., et al., 2015
[58] Stopp M., et al., 2020
[59] Stroebel D., et al., 2007
[60] Su CC., et al., 2006
[61] Su CC., et al., 2007
[62] Takatsuka Y., et al., 2010
[63] Takatsuka Y., et al., 2007
[64] Takatsuka Y., et al., 2010
[65] Tikhonova EB., et al., 2011
[66] Tornroth-Horsefield S., et al., 2007
[67] Vargiu AV., et al., 2011
[68] Vargiu AV., et al., 2012
[69] Vargiu AV., et al., 2014
[70] Wang B., et al., 2015
[71] Wang Y., et al., 2020
[72] Wang Y., et al., 2017
[73] Wang Z., et al., 2015
[74] Weeks JW., et al., 2014
[75] Yamane T., et al., 2013
[76] Yao X., et al., 2020
[77] Yao XQ., et al., 2010
[78] Yao XQ., et al., 2013
[79] Ye C., et al., 2014
[80] Ye C., et al., 2014
[81] Yu EW., et al., 2005
[82] Yu EW., et al., 2003
[83] Yu L., et al., 2011
[84] Yue Z., et al., 2017
[85] Zgurskaya HI. 2009
[86] Zhang XC., et al., 2017
[87] Zuo Z., et al., 2015
[88] Zuo Z., et al., 2016
[89] Zwama M., et al., 2017
External database links:  
ALPHAFOLD:
 P31224
DIP:
 DIP-9049N
ECOCYC:
 ACRB-MONOMER
ECOLIWIKI:
 b0462
INTERPRO:
 IPR001036
INTERPRO:
 IPR027463
INTERPRO:
 IPR004764
MINT:
 P31224
MODBASE:
 P31224
PANTHER:
 PTHR32063
PDB:
 5YIL
PDB:
 6BAJ
PDB:
 6CSX
PDB:
 6Q4N
PDB:
 6Q4O
PDB:
 6Q4P
PDB:
 6SGR
PDB:
 6SGS
PDB:
 6SGT
PDB:
 6SGU
PDB:
 1IWG
PDB:
 1OY6
PDB:
 1OY8
PDB:
 1OY9
PDB:
 1OYD
PDB:
 1OYE
PDB:
 1T9T
PDB:
 1T9U
PDB:
 1T9V
PDB:
 1T9W
PDB:
 1T9X
PDB:
 1T9Y
PDB:
 2DHH
PDB:
 2DR6
PDB:
 2DRD
PDB:
 2GIF
PDB:
 2HQC
PDB:
 2HQD
PDB:
 2HQF
PDB:
 2HQG
PDB:
 2HRT
PDB:
 2I6W
PDB:
 2J8S
PDB:
 2RDD
PDB:
 2W1B
PDB:
 3AOA
PDB:
 3AOB
PDB:
 3AOC
PDB:
 3AOD
PDB:
 3D9B
PDB:
 3NOC
PDB:
 3NOG
PDB:
 3W9H
PDB:
 4C48
PDB:
 4CDI
PDB:
 4DX5
PDB:
 4DX6
PDB:
 4DX7
PDB:
 4K7Q
PDB:
 4U8V
PDB:
 4U8Y
PDB:
 4U95
PDB:
 4U96
PDB:
 4ZIT
PDB:
 4ZIV
PDB:
 4ZIW
PDB:
 4ZJL
PDB:
 4ZJO
PDB:
 4ZJQ
PDB:
 4ZLJ
PDB:
 4ZLL
PDB:
 4ZLN
PDB:
 5EN5
PDB:
 5ENO
PDB:
 5ENP
PDB:
 5ENQ
PDB:
 5ENR
PDB:
 5ENS
PDB:
 5ENT
PDB:
 5JMN
PDB:
 5NC5
PDB:
 5NG5
PDB:
 5O66
PDB:
 5V5S
PFAM:
 PF00873
PRIDE:
 P31224
PRINTS:
 PR00702
PRODB:
 PRO_000022049
REFSEQ:
 NP_414995
SMR:
 P31224
UNIPROT:
 P31224


Operon      
Name: acrAB         
Operon arrangement:
Transcription unit        Promoter
acrB
acrAB


Transcriptional Regulation      
Display Regulation             
Activated by: MarA, Rob, SoxS
Repressed by: MprA, EnvR, PhoP, AcrR


Elements in the selected gene context region unrelated to any object in RegulonDB      

  Type Name Post Left Post Right Strand Notes Evidence (Confirmed, Strong, Weak) References
  promoter TSS_613 480423 reverse nd [RS-EPT-CBR] [90]
  promoter TSS_614 480431 reverse nd [RS-EPT-CBR] [90]
  promoter TSS_615 (cluster) 480436 reverse nd [RS-EPT-CBR] [90]
  promoter hhap6 480503 reverse nd [COMP-AINF] [91]
  promoter TSS_616 480795 reverse nd [RS-EPT-CBR] [90]
  promoter TSS_617 482380 reverse nd [RS-EPT-CBR] [90]
  promoter TSS_618 482514 reverse nd [RS-EPT-CBR] [90]
  promoter TSS_619 482517 reverse nd [RS-EPT-CBR] [90]
  promoter TSS_620 482528 reverse nd [RS-EPT-CBR] [90]
  promoter TSS_621 483377 reverse nd [RS-EPT-CBR] [90]
  promoter TSS_622 483477 reverse nd [RS-EPT-CBR] [90]


Evidence    

 [RS-EPT-CBR] RNA-seq using two enrichment strategies for primary transcripts and consistent biological replicates

 [COMP-AINF] Inferred computationally without human oversight


Reference(s)    

 [1] Ababou A., 2018, New insights into the structural and functional involvement of the gate loop in AcrB export activity., Biochim Biophys Acta 1866(2):242-253

 [2] Adler M., Anjum M., Andersson DI., Sandegren L., 2016, Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli., J Antimicrob Chemother 71(5):1188-98

 [3] Alon Cudkowicz N., Schuldiner S., 2019, Deletion of the major Escherichia coli multidrug transporter AcrB reveals transporter plasticity and redundancy in bacterial cells., PLoS One 14(6):e0218828

 [4] Aoki SK., Malinverni JC., Jacoby K., Thomas B., Pamma R., Trinh BN., Remers S., Webb J., Braaten BA., Silhavy TJ., Low DA., 2008, Contact-dependent growth inhibition requires the essential outer membrane protein BamA (YaeT) as the receptor and the inner membrane transport protein AcrB., Mol Microbiol 70(2):323-40

 [5] Atzori A., Malloci G., Cardamone F., Bosin A., Vargiu AV., Ruggerone P., 2020, Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli., Int J Mol Sci 21(3)

 [6] Atzori A., Malloci G., Prajapati JD., Basciu A., Bosin A., Kleinekathofer U., Dreier J., Vargiu AV., Ruggerone P., 2019, Molecular Interactions of Cephalosporins with the Deep Binding Pocket of the RND Transporter AcrB., J Phys Chem B 123(22):4625-4635

 [7] Atzori A., Malviya VN., Malloci G., Dreier J., Pos KM., Vargiu AV., Ruggerone P., 2019, Identification and characterization of carbapenem binding sites within the RND-transporter AcrB., Biochim Biophys Acta Biomembr 1861(1):62-74

 [8] Bohnert JA., Schuster S., Kern WV., 2013, Pimozide Inhibits the AcrAB-TolC Efflux Pump in Escherichia coli., Open Microbiol J 7:83-6

 [9] Bohnert JA., Schuster S., Seeger MA., Fahnrich E., Pos KM., Kern WV., 2008, Site-directed mutagenesis reveals putative substrate binding residues in the Escherichia coli RND efflux pump AcrB., J Bacteriol 190(24):8225-9

 [10] Bohnert JA., Schuster S., Szymaniak-Vits M., Kern WV., 2011, Determination of real-time efflux phenotypes in Escherichia coli AcrB binding pocket phenylalanine mutants using a 1,2'-dinaphthylamine efflux assay., PLoS One 6(6):e21196

 [11] Brandstatter L., Sokolova L., Eicher T., Seeger MA., Briand C., Cha HJ., Cernescu M., Bohnert J., Kern WV., Brutschy B., Pos KM., 2011, Analysis of AcrB and AcrB/DARPin ligand complexes by LILBID MS., Biochim Biophys Acta 1808(9):2189-96

 [12] Das D., Xu QS., Lee JY., Ankoudinova I., Huang C., Lou Y., DeGiovanni A., Kim R., Kim SH., 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(3):494-502

 [13] Elkins CA., Nikaido H., 2003, Chimeric analysis of AcrA function reveals the importance of its C-terminal domain in its interaction with the AcrB multidrug efflux pump., J Bacteriol 185(18):5349-56

 [14] Fang J., Yu L., Wu M., Wei Y., 2013, Dissecting the function of a protruding loop in AcrB trimerization., J Biomol Struct Dyn 31(4):385-92

 [15] Feng Z., Hou T., Li Y., 2012, Unidirectional peristaltic movement in multisite drug binding pockets of AcrB from molecular dynamics simulations., Mol Biosyst 8(10):2699-709

 [16] Fischer N., Kandt C., 2013, Porter domain opening and closing motions in the multi-drug efflux transporter AcrB., Biochim Biophys Acta 1828(2):632-41

 [17] Fisher MA., Boyarskiy S., Yamada MR., Kong N., Bauer S., Tullman-Ercek D., 2014, Enhancing tolerance to short-chain alcohols by engineering the Escherichia coli AcrB efflux pump to secrete the non-native substrate n-butanol., ACS Synth Biol 3(1):30-40

 [18] Glover CA., Postis VL., Charalambous K., Tzokov SB., Booth WI., Deacon SE., Wallace BA., Baldwin SA., Bullough PA., 2011, AcrB contamination in 2-D crystallization of membrane proteins: lessons from a sodium channel and a putative monovalent cation/proton antiporter., J Struct Biol 176(3):419-24

 [19] Grimsey EM., Fais C., Marshall RL., Ricci V., Ciusa ML., Stone JW., Ivens A., Malloci G., Ruggerone P., Vargiu AV., Piddock LJV., 2020, Chlorpromazine and Amitriptyline Are Substrates and Inhibitors of the AcrB Multidrug Efflux Pump., mBio 11(3)

 [20] Hung LW., Kim HB., Murakami S., Gupta G., Kim CY., Terwilliger TC., 2013, Crystal structure of AcrB complexed with linezolid at 3.5 Å resolution., J Struct Funct Genomics 14(2):71-5

 [21] Husain F., Nikaido H., 2010, Substrate path in the AcrB multidrug efflux pump of Escherichia coli., Mol Microbiol 78(2):320-30

 [22] Iyer R., Ferrari A., Rijnbrand R., Erwin AL., 2015, A fluorescent microplate assay quantifies bacterial efflux and demonstrates two distinct compound binding sites in AcrB., Antimicrob Agents Chemother 59(4):2388-97

 [23] Jahn LJ., Munck C., Ellabaan MMH., Sommer MOA., 2017, Adaptive Laboratory Evolution of Antibiotic Resistance Using Different Selection Regimes Lead to Similar Phenotypes and Genotypes., Front Microbiol 8:816

 [24] Jewel Y., Liu J., Dutta P., 2017, Coarse-grained simulations of conformational changes in the multidrug efflux transporter AcrB., Mol Biosyst 13(10):2006-2014

 [25] Jewel Y., Van Dinh Q., Liu J., Dutta P., 2020, Substrate-dependent transport mechanism in AcrB of multidrug resistant bacteria., Proteins 88(7):853-864

 [26] Kinana AD., Vargiu AV., May T., Nikaido H., 2016, Aminoacyl β-naphthylamides as substrates and modulators of AcrB multidrug efflux pump., Proc Natl Acad Sci U S A 113(5):1405-10

 [27] Kinana AD., Vargiu AV., Nikaido H., 2016, Effect of site-directed mutations in multidrug efflux pump AcrB examined by quantitative efflux assays., Biochem Biophys Res Commun 480(4):552-557

 [28] Kobayashi N., Tamura N., van Veen HW., Yamaguchi A., Murakami S., 2014, β-Lactam selectivity of multidrug transporters AcrB and AcrD resides in the proximal binding pocket., J Biol Chem 289(15):10680-90

 [29] Langevin AM., Dunlop MJ., 2018, Stress Introduction Rate Alters the Benefit of AcrAB-TolC Efflux Pumps., J Bacteriol 200(1)

 [30] Liu M., Zhang XC., 2017, Energy-coupling mechanism of the multidrug resistance transporter AcrB: Evidence for membrane potential-driving hypothesis through mutagenic analysis., Protein Cell 8(8):623-627

 [31] Lu W., Chai Q., Zhong M., Yu L., Fang J., Wang T., Li H., Zhu H., Wei Y., 2012, Assembling of AcrB trimer in cell membrane., J Mol Biol 423(1):123-34

 [32] Lu W., Zhong M., Chai Q., Wang Z., Yu L., Wei Y., 2014, Functional relevance of AcrB Trimerization in pump assembly and substrate binding., PLoS One 9(2):e89143

 [33] Lu W., Zhong M., Wei Y., 2011, A reporter platform for the monitoring of in vivo conformational changes in AcrB., Protein Pept Lett 18(9):863-71

 [34] Lu W., Zhong M., Wei Y., 2011, Folding of AcrB Subunit Precedes Trimerization., J Mol Biol 411(1):264-74

 [35] Ly K., Bartho JD., Eicher T., Pos KM., Mitra AK., 2014, A novel packing arrangement of AcrB in the lipid bilayer membrane., FEBS Lett 588(24):4776-83

 [36] Malvacio I., Buonfiglio R., D'Atanasio N., Serra G., Bosin A., Di Giorgio FP., Ruggerone P., Ombrato R., Vargiu AV., 2019, Molecular basis for the different interactions of congeneric substrates with the polyspecific transporter AcrB., Biochim Biophys Acta Biomembr 1861(7):1397-1408

 [37] Marshall RL., Lloyd GS., Lawler AJ., Element SJ., Kaur J., Ciusa ML., Ricci V., Tschumi A., Kuhne H., Alderwick LJ., Piddock LJV., 2020, New Multidrug Efflux Inhibitors for Gram-Negative Bacteria., mBio 11(4)

 [38] Mishima H., Oshima H., Yasuda S., Kinoshita M., 2015, Statistical thermodynamics for functionally rotating mechanism of the multidrug efflux transporter AcrB., J Phys Chem B 119(8):3423-33

 [39] Mowla R., Wang Y., Ma S., Venter H., 2018, Kinetic analysis of the inhibition of the drug efflux protein AcrB using surface plasmon resonance., Biochim Biophys Acta 1860(4):878-886

 [40] Muller RT., Travers T., Cha HJ., Phillips JL., Gnanakaran S., Pos KM., 2017, Switch Loop Flexibility Affects Substrate Transport of the AcrB Efflux Pump., J Mol Biol 429(24):3863-3874

 [41] Murakami S., Tamura N., Saito A., Hirata T., Yamaguchi A., 2004, Extramembrane central pore of multidrug exporter AcrB in Escherichia coli plays an important role in drug transport., J Biol Chem 279(5):3743-8

 [42] Nakashima R., Sakurai K., Yamaguchi A., 2018, Crystallographic Analysis of Drug and Inhibitor-Binding Structure of RND-Type Multidrug Exporter AcrB in Physiologically Relevant Asymmetric Crystals., Methods Mol Biol 1700:25-36

 [43] Nikaido H., 2018, Covalently Linked Trimers of RND (Resistance-Nodulation-Division) Efflux Transporters to Study Their Mechanism of Action: Escherichia coli AcrB Multidrug Exporter as an Example., Methods Mol Biol 1700:147-165

 [44] Opperman TJ., Kwasny SM., Kim HS., Nguyen ST., Houseweart C., D'Souza S., Walker GC., Peet NP., Nikaido H., Bowlin TL., 2014, Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli., Antimicrob Agents Chemother 58(2):722-33

 [45] Polyak SW., Mowla R., Venter H., 2020, Measuring Small Molecule Binding to Escherichia coli AcrB by Surface Plasmon Resonance., Methods Mol Biol 119-130

 [46] Pos KM., Schiefner A., Seeger MA., Diederichs K., 2004, Crystallographic analysis of AcrB., FEBS Lett 564(3):333-9

 [47] Ramaswamy VK., Vargiu AV., Malloci G., Dreier J., Ruggerone P., 2017, Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters., Sci Rep 7(1):8075

 [48] Reading E., Ahdash Z., Fais C., Ricci V., Wang-Kan X., Grimsey E., Stone J., Malloci G., Lau AM., Findlay H., Konijnenberg A., Booth PJ., Ruggerone P., Vargiu AV., Piddock LJV., Politis A., 2020, Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB., Nat Commun 11(1):5565

 [49] Schmidt TH., Raunest M., Fischer N., Reith D., Kandt C., 2016, Computer simulations suggest direct and stable tip to tip interaction between the outer membrane channel TolC and the isolated docking domain of the multidrug RND efflux transporter AcrB., Biochim Biophys Acta 1858(7 Pt A):1419-26

 [50] Schuldiner S., 2018, The Escherichia coli effluxome., Res Microbiol 169(7-8):357-362

 [51] Schulz R., Vargiu AV., Collu F., Kleinekathofer U., Ruggerone P., 2010, Functional rotation of the transporter AcrB: insights into drug extrusion from simulations., PLoS Comput Biol 6(6):e1000806

 [52] Schulz R., Vargiu AV., Ruggerone P., Kleinekathofer U., 2011, Role of water during the extrusion of substrates by the efflux transporter AcrB., J Phys Chem B 115(25):8278-87

 [53] Schulz R., Vargiu AV., Ruggerone P., Kleinekathofer U., 2015, Computational study of correlated domain motions in the AcrB efflux transporter., Biomed Res Int 487298

 [54] Schuster S., Vavra M., Kern WV., 2016, Evidence of a Substrate-Discriminating Entrance Channel in the Lower Porter Domain of the Multidrug Resistance Efflux Pump AcrB., Antimicrob Agents Chemother 60(7):4315-23

 [55] Simsir M., Broutin I., Mus-Veteau I., Cazals F., 2021, Studying dynamics without explicit dynamics: A structure-based study of the export mechanism by AcrB., Proteins 89(3):259-275

 [56] Sjuts H., Vargiu AV., Kwasny SM., Nguyen ST., Kim HS., Ding X., Ornik AR., Ruggerone P., Bowlin TL., Nikaido H., Pos KM., Opperman TJ., 2016, Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives., Proc Natl Acad Sci U S A 113(13):3509-14

 [57] Soparkar K., Kinana AD., Weeks JW., Morrison KD., Nikaido H., Misra R., 2015, Reversal of the Drug Binding Pocket Defects of the AcrB Multidrug Efflux Pump Protein of Escherichia coli., J Bacteriol 197(20):3255-64

 [58] Stopp M., Steinmetz PA., Schubert C., Griesinger C., Schneider D., Unden G., 2020, Transmembrane signaling and cytoplasmic signal conversion by dimeric transmembrane helix 2 and a linker domain of the DcuS sensor kinase., J Biol Chem

 [59] Stroebel D., Sendra V., Cannella D., Helbig K., Nies DH., Coves J., 2007, Oligomeric behavior of the RND transporters CusA and AcrB in micellar solution of detergent., Biochim Biophys Acta 1768(6):1567-73

 [60] Su CC., Li M., Gu R., Takatsuka Y., McDermott G., Nikaido H., Yu EW., 2006, Conformation of the AcrB multidrug efflux pump in mutants of the putative proton relay pathway., J Bacteriol 188(20):7290-6

 [61] Su CC., Nikaido H., Yu EW., 2007, Ligand-transporter interaction in the AcrB multidrug efflux pump determined by fluorescence polarization assay., FEBS Lett 581(25):4972-6

 [62] Takatsuka Y., Chen C., Nikaido H., 2010, Mechanism of recognition of compounds of diverse structures by the multidrug efflux pump AcrB of Escherichia coli., Proc Natl Acad Sci U S A 107(15):6559-65

 [63] Takatsuka Y., Nikaido H., 2007, Site-directed disulfide cross-linking shows that cleft flexibility in the periplasmic domain is needed for the multidrug efflux pump AcrB of Escherichia coli., J Bacteriol 189(23):8677-84

 [64] Takatsuka Y., Nikaido H., 2010, Site-directed disulfide cross-linking to probe conformational changes of a transporter during its functional cycle: Escherichia coli AcrB multidrug exporter as an example., Methods Mol Biol 634:343-54

 [65] Tikhonova EB., Yamada Y., Zgurskaya HI., 2011, Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC., Chem Biol 18(4):454-63

 [66] Tornroth-Horsefield S., Gourdon P., Horsefield R., Brive L., Yamamoto N., Mori H., Snijder A., Neutze R., 2007, Crystal structure of AcrB in complex with a single transmembrane subunit reveals another twist., Structure 15(12):1663-73

 [67] Vargiu AV., Collu F., Schulz R., Pos KM., Zacharias M., Kleinekathofer U., Ruggerone P., 2011, Effect of the F610A mutation on substrate extrusion in the AcrB transporter: explanation and rationale by molecular dynamics simulations., J Am Chem Soc 133(28):10704-7

 [68] Vargiu AV., Nikaido H., 2012, Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations., Proc Natl Acad Sci U S A 109(50):20637-42

 [69] Vargiu AV., Ruggerone P., Opperman TJ., Nguyen ST., Nikaido H., 2014, Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors., Antimicrob Agents Chemother 58(10):6224-34

 [70] Wang B., Weng J., Wang W., 2015, Substrate binding accelerates the conformational transitions and substrate dissociation in multidrug efflux transporter AcrB., Front Microbiol 6:302

 [71] Wang Y., Alenzy R., Song D., Liu X., Teng Y., Mowla R., Ma Y., Polyak SW., Venter H., Ma S., 2020, Structural optimization of natural product nordihydroguaretic acid to discover novel analogues as AcrB inhibitors., Eur J Med Chem 186:111910

 [72] Wang Y., Mowla R., Guo L., Ogunniyi AD., Rahman T., De Barros Lopes MA., Ma S., Venter H., 2017, Evaluation of a series of 2-napthamide derivatives as inhibitors of the drug efflux pump AcrB for the reversal of antimicrobial resistance., Bioorg Med Chem Lett 27(4):733-739

 [73] Wang Z., Zhong M., Lu W., Chai Q., Wei Y., 2015, Repressive mutations restore function-loss caused by the disruption of trimerization in Escherichia coli multidrug transporter AcrB., Front Microbiol 6:4

 [74] Weeks JW., Bavro VN., Misra R., 2014, Genetic assessment of the role of AcrB β-hairpins in the assembly of the TolC-AcrAB multidrug efflux pump of Escherichia coli., Mol Microbiol 91(5):965-75

 [75] Yamane T., Murakami S., Ikeguchi M., 2013, Functional rotation induced by alternating protonation states in the multidrug transporter AcrB: all-atom molecular dynamics simulations., Biochemistry 52(43):7648-58

 [76] Yao X., Fan X., Yan N., 2020, Cryo-EM analysis of a membrane protein embedded in the liposome., Proc Natl Acad Sci U S A 117(31):18497-18503

 [77] Yao XQ., Kenzaki H., Murakami S., Takada S., 2010, Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations., Nat Commun 1:117

 [78] Yao XQ., Kimura N., Murakami S., Takada S., 2013, Drug uptake pathways of multidrug transporter AcrB studied by molecular simulations and site-directed mutagenesis experiments., J Am Chem Soc 135(20):7474-85

 [79] Ye C., Wang Z., Lu W., Wei Y., 2014, Unfolding study of a trimeric membrane protein AcrB., Protein Sci 23(7):897-905

 [80] Ye C., Wang Z., Lu W., Zhong M., Chai Q., Wei Y., 2014, Correlation between AcrB trimer association affinity and efflux activity., Biochemistry 53(23):3738-46

 [81] Yu EW., Aires JR., McDermott G., Nikaido H., 2005, A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study., J Bacteriol 187(19):6804-15

 [82] Yu EW., McDermott G., Zgurskaya HI., Nikaido H., Koshland DE., 2003, Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump., Science 300(5621):976-80

 [83] Yu L., Lu W., Wei Y., 2011, AcrB trimer stability and efflux activity, insight from mutagenesis studies., PLoS One 6(12):e28390

 [84] Yue Z., Chen W., Zgurskaya HI., Shen J., 2017, Constant pH Molecular Dynamics Reveals How Proton Release Drives the Conformational Transition of a Transmembrane Efflux Pump., J Chem Theory Comput 13(12):6405-6414

 [85] Zgurskaya HI., 2009, Covalently linked AcrB giant offers a new powerful tool for mechanistic analysis of multidrug efflux in bacteria., J Bacteriol 191(6):1727-8

 [86] Zhang XC., Liu M., Han L., 2017, Energy coupling mechanisms of AcrB-like RND transporters., Biophys Rep 3(4):73-84

 [87] Zuo Z., Wang B., Weng J., Wang W., 2015, Stepwise substrate translocation mechanism revealed by free energy calculations of doxorubicin in the multidrug transporter AcrB., Sci Rep 5:13905

 [88] Zuo Z., Weng J., Wang W., 2016, Insights into the Inhibitory Mechanism of D13-9001 to the Multidrug Transporter AcrB through Molecular Dynamics Simulations., J Phys Chem B 120(9):2145-54

 [89] Zwama M., Hayashi K., Sakurai K., Nakashima R., Kitagawa K., Nishino K., Yamaguchi A., 2017, Hoisting-Loop in Bacterial Multidrug Exporter AcrB Is a Highly Flexible Hinge That Enables the Large Motion of the Subdomains., Front Microbiol 8:2095

 [90] Salgado H, Peralta-Gil M, Gama-Castro S, Santos-Zavaleta A, Muñiz-Rascado L, García-Sotelo JS, Weiss V, Solano-Lira H, Martínez-Flores I, Medina-Rivera A, Salgado-Osorio G, Alquicira-Hernández S, Alquicira-Hernández K, López-Fuentes A, Porrón-Sotelo L, Huerta AM, Bonavides-Martínez C, Balderas-Martínez YI, Pannier L, Olvera M, Labastida A, Jiménez-Jacinto V, Vega-Alvarado L, Del Moral-Chávez V, Hernández-Alvarez A, Morett E, Collado-Vides J., 2012, RegulonDB v8.0: omics data sets, evolutionary conservation, regulatory phrases, cross-validated gold standards and more., Nucleic Acids Res.

 [91] Huerta AM., Collado-Vides J., 2003, Sigma70 promoters in Escherichia coli: specific transcription in dense regions of overlapping promoter-like signals., J Mol Biol 333(2):261-78

RegulonDB