Multidrug transporter ABCG2
|Jackson Scott||Postdoctoral Fellow|
|Kowal Julia||Postdoctoral Fellow|
|Manolaridis Ioannis||Postdoctoral Fellow|
|Adaixo Ricardo||Ph.D. Student|
|Zechner Melanie||Ph.D. Student|
ATP-binding cassette (ABC) transmembrane proteins use the energy of bound ATP to drive the transport of many hydrophobic substances, including lipids, across cell membranes. One member of the protein family, ABCG2, is a multi-drug transporter with a physiological role in many tissues. In addition, ABCG2 also extrudes diverse drugs from cancer cells, which can result in multi-drug resistance (MDR), a serious obstacle in cancer treatment. ABCG2 also affects the oral availability of drugs through its function in the gastrointestinal tract, whereas when expressed in liver or kidney cells, it can secrete diverse compounds into bile or urine. ABCG2 and related ABC transporters therefore have an important effect on the pharmacokinetics of drugs. Despite their clinical relevance, the mechanisms of substrate transport and inhibition of ABC transporters are insufficiently understood. The collaborative goal of this project is to establish the structural basis of substrate recognition and transport and modes of inhibition of ABCG2 through a combination of structural studies, functional investigations, and the generation of synthetic compounds and protein binders that can provide mechanistic insight and serve as potential tool compounds for future applications.