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La multiplicité de transport de la P-glycoprotéine : Etudes de modélisation comparative et de docking au sein de la famille des protéines ABC

Abstract : Some ATP-binding-cassette (ABC) transporters confer multidrug resistance (MDR) to pathogenic microorganisms and human tumor cells by mediating the extrusion of a variety of chemotherapeutic drugs out of the cell. One major resistance to chemotherapy has been correlated with the presence of these ABC transporters, acting as molecular " pumps " that actively transport drugs out of the cell, the most prevalent of these being P-glycoprotein (P-gp). Although the X-ray structures of two bacterial ABC proteins have been determined, and the first structures of mouse Pgp released recently in the Protein Data Bank (PDB), establishing molecular structures of human P-gp is still of particular interest because of its clinical relevance. Using homology modeling tools, we rebuilt three structures of human P-gp in different conformations: one nucleotide-bound and two in the absence of nucleotide. Nucleotide binding swaps the accessibility of the transporter from cytoplasmic (inward) facing to extracellular (outward) facing. We placed the three modeled conformational states in a native-like membrane environment, in order to locate several known mutations that alter specificity of drug binding, in particular relatively to the membrane surroundings. We then rebuilt two modeled structures of hamster P-gp in inward and outward conformations, and conducted docking studies of three molecules without any structural similarity (verapamil, vinblastine and tentoxin), but having competitive, non competitive and partial overlapping binding modes. The best poses obtained are consistent with the existence of two different pharmacophores for the recognition of the drug transported by P-glycoprotein.
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https://tel.archives-ouvertes.fr/tel-00711662
Contributor : Celine Lentz <>
Submitted on : Monday, June 25, 2012 - 3:19:20 PM
Last modification on : Wednesday, December 9, 2020 - 3:12:08 PM
Long-term archiving on: : Wednesday, September 26, 2012 - 2:50:23 AM

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  • HAL Id : tel-00711662, version 1

Citation

Anis Bessadok. La multiplicité de transport de la P-glycoprotéine : Etudes de modélisation comparative et de docking au sein de la famille des protéines ABC. Bio-Informatique, Biologie Systémique [q-bio.QM]. Université Pierre et Marie Curie - Paris VI, 2011. Français. ⟨tel-00711662⟩

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