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Suresh V. Ambudkar, Ph.D.
Project Title: Biochemistry of Multidrug Transporters
ATP-binding cassette (ABC) transporters such as P-glycoprotein (Pgp, ABCB1), the multidrug resistance-associated protein 1 (MRP1, ABCC1), and ABCG2 (MXR, BCRP), which function as ATP-dependent efflux pumps, play an important role in the development of multidrug resistance (MDR) in most cancers. Our current goals are to determine the mechanisms of action of multidrug resistance-linked ABC transporters including Pgp and ABCG2. We are addressing these questions: a) What is the molecular mechanism of the polyspecificity of Pgp? b) How do substrate binding and ATP sites interact? c) How is the energy from ATP hydrolysis used for drug transport? Our long-term goal is to elucidate the role of ABC drug transporters in the development of MDR in cancers and facilitate new therapeutic strategies.
1. Elucidation of the catalytic cycle of ATP hydrolysis and transport pathway of Pgp and role of conserved motifs in the ATP-binding cassette.
2. Development of potent non-toxic small molecule modulators/inhibitors of ABC transporters.
3. Resolution of the three-dimensional structure of human Pgp.
4. Role of intracellular loops 1 and 3 in folding and stability of human Pgp:
These studies should provide insights into the mechanism of action and regulation of these transporters and aid in the development of strategies to increase the efficiency of chemotherapy to treat cancer.
This page was last updated on 4/18/2014.