title: Structural basis for heavy metal detoxification by an Atm1-type ABC exporter.
abstract: Although substantial progress has been achieved in the structural analysis of exporters from the superfamily of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, much less is known about how they selectively recognize substrates and how substrate binding is coupled to ATP hydrolysis. We have addressed these questions through crystallographic analysis of the Atm1/ABCB7/HMT1/ABCB6 ortholog from Novosphingobium aromaticivorans DSM 12444, NaAtm1, at 2.4 angstrom resolution. Consistent with a physiological role in cellular detoxification processes, functional studies showed that glutathione derivatives can serve as substrates for NaAtm1 and that its overexpression in Escherichia coli confers protection against silver and mercury toxicity. The glutathione binding site highlights the articulated design of ABC exporters, with ligands and nucleotides spanning structurally conserved elements to create adaptable interfaces accommodating conformational rearrangements during the transport cycle.
authors.affiliation: Howard Hughes Medical Institute and Division of Chemistry and Chemical Engineering, Mail Code 114-96, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Jonas Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Janet G
authors.initials: JG
authors.lastname: Yang
authors.forename: Daniel
authors.initials: D
authors.lastname: Zhitnitsky
authors.forename: Oded
authors.initials: O
authors.lastname: Lewinson
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Rees
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000737:chemistry; D008658:Inactivation, Metabolic; D019216:Metals, Heavy / Q000378:metabolism* / Q000633:toxicity*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D042301:Sphingomonadaceae / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D019216:Metals, Heavy; D005978:Glutathione