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FEBS J. 2009 Feb;276(4):964-72. doi: 10.1111/j.1742-4658.2008.06832.x.

Data-driven homology modelling of P-glycoprotein in the ATP-bound state indicates flexibility of the transmembrane domains.

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1
Bioresources, Austrian Research Centers GmbH-ARC, Seibersdorf, Austria. thomas.stockner@arcs.ac.at

Abstract

Human P-glycoprotein is an ATP-binding cassette transporter that plays an important role in the defence against potentially harmful molecules from the environment. It is involved in conferring resistance against cancer therapeutics and plays an important role for the pharmacokinetics of drugs. The lack of a high resolution structure of P-glycoprotein has hindered its functional understanding and represents an obstacle for structure based drug development. The homologous bacterial exporter Sav1866 has been shown to share a common architecture and overlapping substrate specificity with P-glycoprotein. The structure of Sav1866 suggests that helices in the transmembrane domains diverge at the extracytoplasmic face, whereas cross-link information and a combination of small angle X-ray scattering and cryo-electron crystallography data indicate that helices 6 and 12 of P-glycoprotein are closer in P-glycoprotein than in the crystal structure of Sav1866. Using homology modelling, we present evidence that the protein possesses intrinsic structural flexibility to allow cross-links to occur between helices 6 and 12 of P-glycoprotein, thereby reconciling crystallographic models with available experimental data from cross-linking.

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