Structures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states.

TitleStructures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states.
Publication TypeJournal Article
Year of Publication2013
AuthorsShintre, CA, Pike, ACW, Li, Q, Kim, J-I, Barr, AJ, Goubin, S, Shrestha, L, Yang, J, Berridge, G, Ross, J, Stansfeld, PJ, Sansom, MSP, Edwards, AM, Bountra, C, Marsden, BD, von Delft, F, Bullock, AN, Gileadi, O, Burgess-Brown, NA, Carpenter, EP
JournalProc Natl Acad Sci U S A
Volume110
Issue24
Pagination9710-5
Date Published2013 Jun 11
ISSN1091-6490
KeywordsAdenosine Triphosphatases, Adenosine Triphosphate, Amino Acid Sequence, Animals, ATP-Binding Cassette Transporters, Binding Sites, Crystallography, X-Ray, Humans, Lipid Bilayers, Models, Molecular, Molecular Conformation, Molecular Dynamics Simulation, Molecular Sequence Data, Mutation, Nucleotides, Phosphatidylcholines, Phosphatidylethanolamines, Protein Binding, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Sf9 Cells
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.

DOI10.1073/pnas.1217042110
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.1217042110
PubMed ID23716676
PubMed Central IDPMC3683770
Grant List092809 / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
/ / Canadian Institutes of Health Research / Canada