title: An allosteric transport mechanism for the AcrAB-TolC multidrug efflux pump.
abstract: Bacterial efflux pumps confer multidrug resistance by transporting diverse antibiotics from the cell. In Gram-negative bacteria, some of these pumps form multi-protein assemblies that span the cell envelope. Here, we report the near-atomic resolution cryoEM structures of theEscherichia coliAcrAB-TolC multidrug efflux pump in resting and drug transport states, revealing a quaternary structural switch that allosterically couples and synchronizes initial ligand binding with channel opening. Within the transport-activated state, the channel remains open even though the pump cycles through three distinct conformations. Collectively, our data provide a dynamic mechanism for the assembly and operation of the AcrAB-TolC pump.
authors.affiliation: National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, United States.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Health Science Center at Houston Medical School, Houston, United States.
authors.forename: Guizhen
authors.initials: G
authors.lastname: Fan
authors.affiliation: National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, United States.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.|Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, United States.
authors.forename: Corey F
authors.identifier: 0000-0002-7277-5249
authors.initials: CF
authors.lastname: Hryc
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: James N
authors.identifier: 0000-0001-5420-2116
authors.initials: JN
authors.lastname: Blaza
authors.affiliation: Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Health Science Center at Houston Medical School, Houston, United States.
authors.forename: Irina I
authors.initials: II
authors.lastname: Serysheva
authors.affiliation: National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, United States.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Schmid
authors.affiliation: National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, United States.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.|Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, United States.
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ben F
authors.identifier: 0000-0003-1144-9877
authors.initials: BF
authors.lastname: Luisi
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Dijun
authors.initials: D
authors.lastname: Du
mesh_terms: D000494:Allosteric Regulation; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D004926:Escherichia coli / Q000737:chemistry / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: C000596829:AcrAB-TolC protein, E coli; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D029968:Escherichia coli Proteins
keywords: AcrA; AcrZ; Carb; E. coli; TolC; biophysics; drug efflux; structural biology; tripartite assembly