AI Article Synopsis
- BCRP/ABCG2 is involved in transporting drugs and xenobiotics out of cells, and was successfully expressed and purified in Pichia pastoris for study.
- Crystallization of BCRP produced two-dimensional crystals that were analyzed with cryo-electron microscopy, revealing different structural forms depending on the presence of the drug mitoxantrone.
- Using homology modeling, researchers created models of BCRP's open (substrate-free) and closed (substrate-bound) states, which align with observed changes in structure upon drug binding.
Article Abstract
BCRP/ABCG2 mediates efflux of drugs and xenobiotics. BCRP was expressed in Pichia pastoris, purified to > 90% homogeneity, and subjected to two-dimensional (2D) crystallization. The 2D crystals showed a p12(1) symmetry and projection maps were determined at 5 A resolution by cryo-electron microscopy. Two crystal forms with and without mitoxantrone were observed with unit cell dimensions of a = 55.4 A, b = 81.4 A, gamma = 89.8 degrees , and a = 57.3 A, b = 88.0 A, gamma = 89.7 degrees , respectively. The projection map without mitoxantrone revealed an asymmetric structure with ring-shaped density features probably corresponding to a bundle of transmembrane alpha helices, and appeared more open and less symmetric than the map with mitroxantrone. The open and closed inward-facing forms of BCRP were generated by homology modeling, representing the substrate-free and substrate-bound conformations in the absence of nucleotide, respectively. These models are consistent with the experimentally observed conformational change upon substrate binding.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858361 | PMC |
| http://dx.doi.org/10.1016/j.str.2010.01.017 | DOI Listing |
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