title: Switch-loop flexibility affects transport of large drugs by the promiscuous AcrB multidrug efflux transporter.
abstract: Multidrug efflux transporters recognize a variety of structurally unrelated compounds for which the molecular basis is poorly understood. For the resistance nodulation and cell division (RND) inner membrane component AcrB of the AcrAB-TolC multidrug efflux system from Escherichia coli, drug binding occurs at the access and deep binding pockets. These two binding areas are separated by an 11-amino-acid-residue-containing switch loop whose conformational flexibility is speculated to be essential for drug binding and transport. A G616N substitution in the switch loop has a distinct and local effect on the orientation of the loop and on the ability to transport larger drugs. Here, we report a distinct phenotypical pattern of drug recognition and transport for the G616N variant, indicating that drug substrates with minimal projection areas of >70 Å(2) are less well transported than other substrates.
authors.affiliation: Institute of Biochemistry, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Hi-jea
authors.initials: HJ
authors.lastname: Cha
authors.affiliation: Institute of Biochemistry, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Reinke T
authors.initials: RT
authors.lastname: Müller
authors.affiliation: Institute of Biochemistry, Goethe University Frankfurt, Frankfurt am Main, Germany pos@em.uni-frankfurt.de.
authors.forename: Klaas M
authors.initials: KM
authors.lastname: Pos
mesh_terms: D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001692:Biological Transport; D018360:Crystallography, X-Ray; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D008970:Molecular Weight; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015262:Xenobiotics / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004317:Doxorubicin; D029968:Escherichia coli Proteins; D008911:Minocycline; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015262:Xenobiotics; C083496:AcrB protein, E coli