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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.

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

06/2013

Volume

110

Pages

9710 - 9715

Addresses

Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.

Keywords

Animals, Humans, Nucleotides, Lipid Bilayers, Phosphatidylcholines, Phosphatidylethanolamines, ATP-Binding Cassette Transporters, Adenosine Triphosphate, Crystallography, X-Ray, Binding Sites, Amino Acid Sequence, Molecular Conformation, Protein Structure, Tertiary, Protein Binding, Sequence Homology, Amino Acid, Mutation, Models, Molecular, Molecular Sequence Data, Adenosine Triphosphatases, Molecular Dynamics Simulation, Sf9 Cells