Open AccessThree‐dimensional structure of the human breast cancer resistance protein (BCRP/ABCG2) in an inward‐facing conformation
Author(s) -
Rosenberg Mark F.,
Bikadi Zsolt,
Hazai Eszter,
Starborg Tobias,
Kelley Lawrence,
Chayen Naomi E.,
Ford Robert C.,
Mao Qingcheng
Publication year - 2015
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s1399004715010676
Subject(s) - abcg2 , atp binding cassette transporter , transmembrane domain , efflux , chemistry , transporter , protein structure , stereochemistry , crystallography , biophysics , biology , biochemistry , amino acid , gene
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.