title: Structures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states.
abstract: ABCB10 is one of the three ATP-binding cassette (ABC) transporters found in the inner membrane of mitochondria. In mammals ABCB10 is essential for erythropoiesis, and for protection of mitochondria against oxidative stress. ABCB10 is therefore a potential therapeutic target for diseases in which increased mitochondrial reactive oxygen species production and oxidative stress play a major role. The crystal structure of apo-ABCB10 shows a classic exporter fold ABC transporter structure, in an open-inwards conformation, ready to bind the substrate or nucleotide from the inner mitochondrial matrix or membrane. Unexpectedly, however, ABCB10 adopts an open-inwards conformation when complexed with nonhydrolysable ATP analogs, in contrast to other transporter structures which adopt an open-outwards conformation in complex with ATP. The three complexes of ABCB10/ATP analogs reported here showed varying degrees of opening of the transport substrate binding site, indicating that in this conformation there is some flexibility between the two halves of the protein. These structures suggest that the observed plasticity, together with a portal between two helices in the transmembrane region of ABCB10, assist transport substrate entry into the substrate binding cavity. These structures indicate that ABC transporters may exist in an open-inwards conformation when nucleotide is bound. We discuss ways in which this observation can be aligned with the current views on mechanisms of ABC transporters.
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Chitra A
authors.initials: CA
authors.lastname: Shintre
authors.forename: Ashley C W
authors.initials: AC
authors.lastname: Pike
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
authors.forename: Jung-In
authors.initials: JI
authors.lastname: Kim
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Barr
authors.forename: Solenne
authors.initials: S
authors.lastname: Goubin
authors.forename: Leela
authors.initials: L
authors.lastname: Shrestha
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Georgina
authors.initials: G
authors.lastname: Berridge
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ross
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stansfeld
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
authors.forename: Aled M
authors.initials: AM
authors.lastname: Edwards
authors.forename: Chas
authors.initials: C
authors.lastname: Bountra
authors.forename: Brian D
authors.initials: BD
authors.lastname: Marsden
authors.forename: Frank
authors.initials: F
authors.lastname: von Delft
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Opher
authors.initials: O
authors.lastname: Gileadi
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Burgess-Brown
authors.forename: Elisabeth P
authors.initials: EP
authors.lastname: Carpenter
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D061987:Sf9 Cells
chemical_list: C412459:ABCB10 protein, human; D018528:ATP-Binding Cassette Transporters; D008051:Lipid Bilayers; D009711:Nucleotides; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C057561:1-palmitoyl-2-oleoylphosphatidylethanolamine; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: ABC mitochondrial erythroid; X-ray crystallography; cardiolipin; human membrane protein structure; nucleotide complex