title: Pseudoatomic Structure of the Tripartite Multidrug Efflux Pump AcrAB-TolC Reveals the Intermeshing Cogwheel-like Interaction between AcrA and TolC.
abstract: The resistance-nodulation-division type tripartite pump AcrAB-TolC and its homologs are responsible for multidrug resistance in Gram-negative bacteria by expelling a wide variety of toxic substrates. The three essential components, AcrA, AcrB, and TolC, must function in concert with each respective binding partner within the complex. In this study, we report an 8.2-Å resolution cryo-electron microscopy (cryo-EM) 3D reconstruction of the complex that consists of an AcrAB fusion protein and a chimeric TolC protein. The pseudoatomic structure derived from the cryo-EM reconstruction clearly demonstrates a model only compatible with the adaptor bridging mechanism, wherein the funnel-like AcrA hexamer forms an intermeshing cogwheel-like interaction with the α-barrel tip region of TolC. These observations provide a structural milestone for understanding multidrug resistance in pathogenic Gram-negative bacteria, and may also lead to the design of new antibacterial drugs.
authors.affiliation: Nano-Bio Electron Microscopy Research Team, Korea Basic Science Institute, Daejeon 305-806, Republic of Korea.
authors.forename: Hyeongseop
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Department of Agricultural Biotechnology, Center for Food and Bioconvergence, Center for Food Safety and Toxicology, Research Institute for Agricultural and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Jin-Sik
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Agricultural Biotechnology, Center for Food and Bioconvergence, Center for Food Safety and Toxicology, Research Institute for Agricultural and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Saemee
authors.initials: S
authors.lastname: Song
authors.affiliation: Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Shigematsu
authors.affiliation: Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Nano-Bio Electron Microscopy Research Team, Korea Basic Science Institute, Daejeon 305-806, Republic of Korea. Electronic address: hjk002@kbsi.re.kr.
authors.forename: Jaekyung
authors.initials: J
authors.lastname: Hyun
authors.affiliation: Department of Agricultural Biotechnology, Center for Food and Bioconvergence, Center for Food Safety and Toxicology, Research Institute for Agricultural and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea. Electronic address: hanc210@snu.ac.kr.
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Ha
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D020285:Cryoelectron Microscopy; D024901:Drug Resistance, Multiple, Bacterial; D006090:Gram-Negative Bacteria / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins
keywords: Complex structure; Cryo-electron microscopy; Membrane protein; Multidrug efflux pump