| Structural highlights
6euq is a 1 chain structure with sequence from Ecoli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , , |
| Gene: | mdfA, cmlA, cmr, b0842, JW0826 (ECOLI) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Publication Abstract from PubMed
Secondary multidrug (Mdr) transporters utilize ion concentration gradients to actively remove antibiotics and other toxic compounds from cells. The model Mdr transporter MdfA from Escherichia coli exchanges dissimilar drugs for protons. The transporter should open at the cytoplasmic side to enable access of drugs into the Mdr recognition pocket. Here we show that the cytoplasmic rim around the Mdr recognition pocket represents a previously overlooked important regulatory determinant in MdfA. We demonstrate that increasing the positive charge of the electrically asymmetric rim dramatically inhibits MdfA activity and sometimes even leads to influx of planar, positively charged compounds, resulting in drug sensitivity. Our results suggest that unlike the mutants with the electrically modified rim, the membrane-embedded wild-type MdfA exhibits a significant probability of an inward-closed conformation, which is further increased by drug binding. Since MdfA binds drugs from its inward-facing environment, these results are intriguing and raise the possibility that the transporter has a sensitive, drug-induced conformational switch, which favors an inward-closed state.
A New Critical Conformational Determinant of Multidrug Efflux by an MFS Transporter.,Zomot E, Yardeni EH, Vargiu AV, Tam HK, Malloci G, Ramaswamy VK, Perach M, Ruggerone P, Pos KM, Bibi E J Mol Biol. 2018 Apr 27;430(9):1368-1385. doi: 10.1016/j.jmb.2018.02.026. Epub, 2018 Mar 9. PMID:29530612[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Zomot E, Yardeni EH, Vargiu AV, Tam HK, Malloci G, Ramaswamy VK, Perach M, Ruggerone P, Pos KM, Bibi E. A New Critical Conformational Determinant of Multidrug Efflux by an MFS Transporter. J Mol Biol. 2018 Apr 27;430(9):1368-1385. doi: 10.1016/j.jmb.2018.02.026. Epub, 2018 Mar 9. PMID:29530612 doi:http://dx.doi.org/10.1016/j.jmb.2018.02.026
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