Abstract
The human breast cancer resistance protein is an ATP-binding cassette (ABC) multidrug transporter that affects the bioavailability of chemotherapeutic drugs and can confer drug resistance on cancer cells. It is the second member of the ABCG subfamily, other members of which are associated with human steroid disorders such as hypercholesterolemia, sitosterolemia, and atherosclerosis. The molecular bases of protein-steroid interactions in ABC transporters are unknown. Here, we identify a steroid-binding element in the membrane domain of ABCG2 with a similarity to steroid hormone/nuclear receptors. The element facilitates steroid hormone binding and mediates modulation of ABCG2 activity. The identification of this element might provide an opportunity for the development of new therapeutic ligands for ABCG2.
Footnotes
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This study was supported by the Medical Research Council and Association for International Cancer Research.
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ABBREVIATIONS: ABC, ATP-binding cassette; a.u., arbitrary unit; DSG, disuccinimidyl glutarate; ED, 17β-estradiol; PG, progesterone; TMH, transmembrane helix; GalP, galactose transporter; LBD, ligand binding domain; hPRβ, human progesterone receptor-β; hERα, human estrogen receptor-α; HEK, human embryonic kidney.
- Received May 18, 2007.
- Accepted October 5, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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