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Acta Crystallogr D Biol Crystallogr. 2015 Aug;71(Pt 8):1725-35. doi: 10.1107/S1399004715010676. Epub 2015 Jul 31.

Three-dimensional structure of the human breast cancer resistance protein (BCRP/ABCG2) in an inward-facing conformation.

Author information

1
Faculty of Life Science, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, England.
2
Virtua Drug Ltd, Budapest 1015, Hungary.
3
Centre for Bioinformatics, Division of Molecular Biosciences, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, England.
4
Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, England.
5
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA.

Abstract

ABCG2 is an efflux drug transporter that plays an important role in drug resistance and drug disposition. In this study, the first three-dimensional structure of human full-length ABCG2 analysed by electron crystallography from two-dimensional crystals in the absence of nucleotides and transported substrates is reported at 2 nm resolution. In this state, ABCG2 forms a symmetric homodimer with a noncrystallographic twofold axis perpendicular to the two-dimensional crystal plane, as confirmed by subtomogram averaging. This configuration suggests an inward-facing configuration similar to murine ABCB1, with the nucleotide-binding domains (NBDs) widely separated from each other. In the three-dimensional map, densities representing the long cytoplasmic extensions from the transmembrane domains that connect the NBDs are clearly visible. The structural data have allowed the atomic model of ABCG2 to be refined, in which the two arms of the V-shaped ABCG2 homodimeric complex are in a more closed and narrower conformation. The structural data and the refined model of ABCG2 are compatible with the biochemical analysis of the previously published mutagenesis studies, providing novel insight into the structure and function of the transporter.

KEYWORDS:

ABC transporter; ABCG2; ATP-binding cassette transporter; BCRP; cryo-electron microscopy; three-dimensional structure from two-dimensional crystals

PMID:
26249353
PMCID:
PMC4528803
DOI:
10.1107/S1399004715010676
[Indexed for MEDLINE]
Free PMC Article

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