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

被引:197
作者
Shintre, Chitra A. [1 ]
Pike, Ashley C. W. [1 ]
Li, Qiuhong [1 ]
Kim, Jung-In [1 ]
Barr, Alastair J. [1 ]
Goubin, Solenne [1 ]
Shrestha, Leela [1 ]
Yang, Jing [1 ]
Berridge, Georgina [1 ]
Ross, Jonathan [1 ]
Stansfeld, Phillip J. [2 ]
Sansom, Mark S. P. [2 ]
Edwards, Aled M. [3 ]
Bountra, Chas [1 ]
Marsden, Brian D. [1 ]
von Delft, Frank [1 ]
Bullock, Alex N. [1 ]
Gileadi, Opher [1 ]
Burgess-Brown, Nicola A. [1 ]
Carpenter, Elisabeth P. [1 ]
机构
[1] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7DQ, England
[2] Univ Oxford, Dept Biochem, Struct & Computat Bioinformat Unit, Oxford OX1 3QU, England
[3] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada
基金
加拿大创新基金会; 英国惠康基金; 英国生物技术与生命科学研究理事会;
关键词
ABC mitochondrial erythroid; X-ray crystallography; human membrane protein structure; nucleotide complex; cardiolipin; P-GLYCOPROTEIN; CRYSTAL-STRUCTURE; RESISTANCE; MECHANISM; MITOCHONDRIA; MITOFERRIN-1; HYDROLYSIS; PROTEINS; REVEALS; COMPLEX;
D O I
10.1073/pnas.1217042110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:9710 / 9715
页数:6
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