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Molecular mechanism of the polyspecificity of the MDR-linked P-glycoprotein (ABCB1)

Monday, October 24, 2011 — Poster Session I

Noon – 2:00 p.m.

Natcher Conference Center




  • EE Chufan
  • K Kapoor
  • S Durell
  • SV Ambudkar


Multidrug resistance (MDR) is a clinical phenomenon in which cells develop resistance to chemically diverse drugs (i.e. polyspecificity). One of the major players in MDR is P-glycoprotein (Pgp, ABCB1), which is a member of the ATP-binding cassette (ABC) transporter superfamily. This transporter utilizes energy from ATP hydrolysis for the efflux of anticancer drugs. We have developed a homology model of human Pgp on the basis of mouse Pgp X-ray structure. In the transmembrane region, the structure exhibits a large conical cavity opened to the cytoplasm and the membrane inner leaflet in what appears to be a drug-binding site. Docking studies at this potential binding site were carried out for several substrates of Pgp as cyclosporine A (CsA), tariquidar (XR-9576), iodoaryl-azidoprazosin (IAAP), verapamil and 5'-fluorosulfonylbenzoyl 5'-adenosine (FSBA). Residues interacting with the substrates in the docking studies were mutated and the mutants overexpressed in High-Five insect cells were submitted to biochemical and functional assays. Preliminary results show a decreased binding affinity for CsA, tariquidar and FSBA in some of the mutants, suggesting that these residues contribute to the drug-binding pocket where several structurally dissimilar compounds can bind.

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