title: Functionality mapping on internal surfaces of multidrug transporter AcrB based on molecular theory of solvation: implications for drug efflux pathway.
abstract: AcrB is a membrane protein and a multidrug efflux transporter. Although the recently solved X-ray crystal structures of AcrB provide a rough sketch of how drugs efflux, the pathway and mechanism have not been completely elucidated. In this study, a ligand-mapping method based on the 3D-RISM molecular theory of solvation, which we recently developed, is applied to AcrB in order to identify the drug efflux pathway. We use a fragment-based approach as a strategy to map chemical functionality on the internal surfaces. A few "multifunctional" ligand-binding sites, which recognize various types of functional groups, are detected inside the porter domain. Spatial links between the multifunctional sites indicate a probable multidrug efflux pathway. The frustrated environment of the protein cavity constructed of weak interactions between ligand and protein may be a mechanism for allowing smooth transportation through the protein. Guided diffusion appears to be the main mechanism for efflux.
authors.affiliation: Quantitative Biology Center, RIKEN, Kobe, Hyogo, Japan. takashi.imai@riken.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Imai
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miyashita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sugita
authors.forename: Andriy
authors.initials: A
authors.lastname: Kovalenko
authors.forename: Fumio
authors.initials: F
authors.lastname: Hirata
authors.forename: Akinori
authors.initials: A
authors.lastname: Kidera
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry*; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry; D017434:Protein Structure, Tertiary; D012997:Solvents / Q000737:chemistry
chemical_list: D029968:Escherichia coli Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D004364:Pharmaceutical Preparations; D012997:Solvents; C083496:AcrB protein, E coli