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| | <StructureSection load='6oop' size='340' side='right'caption='[[6oop]], [[Resolution|resolution]] 2.80Å' scene=''> | | <StructureSection load='6oop' size='340' side='right'caption='[[6oop]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6oop]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OOP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OOP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6oop]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OOP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OOP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=KHJ:1,1-dimethyl-4,4-bipyridin-1-ium'>KHJ</scene>, <scene name='pdbligand=PR:PRASEODYMIUM+ION'>PR</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">A9R57_05385, BJJ90_17655 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KHJ:1,1-dimethyl-4,4-bipyridin-1-ium'>KHJ</scene>, <scene name='pdbligand=PR:PRASEODYMIUM+ION'>PR</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6oop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oop OCA], [http://pdbe.org/6oop PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6oop RCSB], [http://www.ebi.ac.uk/pdbsum/6oop PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6oop ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6oop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oop OCA], [https://pdbe.org/6oop PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oop RCSB], [https://www.ebi.ac.uk/pdbsum/6oop PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oop ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/MDFA_ECOLI MDFA_ECOLI] Efflux pump driven by the proton motive force. Confers resistance to a broad spectrum of chemically unrelated drugs. Confers resistance to a diverse group of cationic or zwitterionic lipophilic compounds such as ethidium bromide, tetraphenylphosphonium, rhodamine, daunomycin, benzalkonium, rifampicin, tetracycline, puromycin, and to chemically unrelated, clinically important antibiotics such as chloramphenicol, erythromycin, and certain aminoglycosides and fluoroquinolones. Overexpression results in isopropyl-beta-D-thiogalactopyranoside (IPTG) exclusion and spectinomycin sensitivity. Transport of neutral substrates is electrogenic, whereas transport of cationic substrates is electroneutral. In addition to its role in multidrug resistance, confers extreme alkaline pH resistance, allowing the growth under conditions that are close to those used normally by alkaliphiles. This activity requires Na(+) or K(+).<ref>PMID:12578981</ref> <ref>PMID:15371593</ref> <ref>PMID:9079913</ref> <ref>PMID:9644262</ref> <ref>PMID:9811673</ref> |
| - | MdfA is a prototypical H(+)-coupled multidrug transporter that is characterized by extraordinarily broad substrate specificity. The involvement of specific H-bonds in MdfA-drug interactions and the simplicity of altering the substrate specificity of MdfA contradict the promiscuous nature of multidrug recognition, presenting a baffling conundrum. Here we show the X-ray structures of MdfA variant I239T/G354E in complexes with three electrically different ligands, determined at resolutions up to 2.2 A. Our structures reveal that I239T/G354E interacts with these compounds differently from MdfA and that I239T/G354E possesses two discrete, non-overlapping substrate-binding sites. Our results shed new light on the molecular design of multidrug-binding and protonation sites and highlight the importance of often-neglected, long-range charge-charge interactions in multidrug recognition. Beyond helping to solve the ostensible conundrum of multidrug recognition, our findings suggest the mechanistic difference between substrate and inhibitor for any H(+)-dependent multidrug transporter, which may open new vistas on curtailing efflux-mediated multidrug resistance.
| + | |
| - | | + | |
| - | Structure of an engineered multidrug transporter MdfA reveals the molecular basis for substrate recognition.,Wu HH, Symersky J, Lu M Commun Biol. 2019 Jun 17;2:210. doi: 10.1038/s42003-019-0446-y. eCollection 2019. PMID:31240248<ref>PMID:31240248</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div> | + | |
| - | <div class="pdbe-citations 6oop" style="background-color:#fffaf0;"></div> | + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus coli migula 1895]] | + | [[Category: Escherichia coli]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lu, M]] | + | [[Category: Lu M]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Transport]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Function
MDFA_ECOLI Efflux pump driven by the proton motive force. Confers resistance to a broad spectrum of chemically unrelated drugs. Confers resistance to a diverse group of cationic or zwitterionic lipophilic compounds such as ethidium bromide, tetraphenylphosphonium, rhodamine, daunomycin, benzalkonium, rifampicin, tetracycline, puromycin, and to chemically unrelated, clinically important antibiotics such as chloramphenicol, erythromycin, and certain aminoglycosides and fluoroquinolones. Overexpression results in isopropyl-beta-D-thiogalactopyranoside (IPTG) exclusion and spectinomycin sensitivity. Transport of neutral substrates is electrogenic, whereas transport of cationic substrates is electroneutral. In addition to its role in multidrug resistance, confers extreme alkaline pH resistance, allowing the growth under conditions that are close to those used normally by alkaliphiles. This activity requires Na(+) or K(+).[1] [2] [3] [4] [5]
References
- ↑ Lewinson O, Adler J, Poelarends GJ, Mazurkiewicz P, Driessen AJ, Bibi E. The Escherichia coli multidrug transporter MdfA catalyzes both electrogenic and electroneutral transport reactions. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1667-72. Epub 2003 Feb 10. PMID:12578981 doi:http://dx.doi.org/10.1073/pnas.0435544100
- ↑ Lewinson O, Padan E, Bibi E. Alkalitolerance: a biological function for a multidrug transporter in pH homeostasis. Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14073-8. Epub 2004 Sep 15. PMID:15371593 doi:http://dx.doi.org/10.1073/pnas.0405375101
- ↑ Edgar R, Bibi E. MdfA, an Escherichia coli multidrug resistance protein with an extraordinarily broad spectrum of drug recognition. J Bacteriol. 1997 Apr;179(7):2274-80. PMID:9079913
- ↑ Mine T, Morita Y, Kataoka A, Mizushima T, Tsuchiya T. Evidence for chloramphenicol/H+ antiport in Cmr (MdfA) system of Escherichia coli and properties of the antiporter. J Biochem. 1998 Jul;124(1):187-93. PMID:9644262
- ↑ Bohn C, Bouloc P. The Escherichia coli cmlA gene encodes the multidrug efflux pump Cmr/MdfA and is responsible for isopropyl-beta-D-thiogalactopyranoside exclusion and spectinomycin sensitivity. J Bacteriol. 1998 Nov;180(22):6072-5. PMID:9811673
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