| Structural highlights
7oul is a 5 chain structure with sequence from Escherichia coli K-12 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.8Å |
| Ligands: | , , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
ACRB_ECOLI AcrAB is a drug efflux protein with a broad substrate specificity.[1] [2] [3]
Publication Abstract from PubMed
Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.
Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps.,Ple C, Tam HK, Vieira Da Cruz A, Compagne N, Jimenez-Castellanos JC, Muller RT, Pradel E, Foong WE, Malloci G, Ballee A, Kirchner MA, Moshfegh P, Herledan A, Herrmann A, Deprez B, Willand N, Vargiu AV, Pos KM, Flipo M, Hartkoorn RC Nat Commun. 2022 Jan 10;13(1):115. doi: 10.1038/s41467-021-27726-2. PMID:35013254[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature. 2006 Sep 14;443(7108):173-9. Epub 2006 Aug 16. PMID:16915237 doi:10.1038/nature05076
- ↑ Seeger MA, Schiefner A, Eicher T, Verrey F, Diederichs K, Pos KM. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science. 2006 Sep 1;313(5791):1295-8. PMID:16946072 doi:313/5791/1295
- ↑ Sennhauser G, Amstutz P, Briand C, Storchenegger O, Grutter MG. Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol. 2007 Jan;5(1):e7. PMID:17194213 doi:10.1371/journal.pbio.0050007
- ↑ Plé C, Tam HK, Vieira Da Cruz A, Compagne N, Jiménez-Castellanos JC, Müller RT, Pradel E, Foong WE, Malloci G, Ballée A, Kirchner MA, Moshfegh P, Herledan A, Herrmann A, Deprez B, Willand N, Vargiu AV, Pos KM, Flipo M, Hartkoorn RC. Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps. Nat Commun. 2022 Jan 10;13(1):115. PMID:35013254 doi:10.1038/s41467-021-27726-2
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