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P-glycoprotein (P-gp) is an ATP-binding cassette transporter that exports a huge range of compounds out of cells and is thus one of the key proteins in conferring multi-drug resistance in cancer. Understanding how it achieves such a broad specificity and the series of conformational changes that allow export to occur form major, on-going, research objectives around the world. Much of our knowledge to date has been derived from mutagenesis and assay data. However, in recent years, there has also been great progress in structural biology and although the structure of human P-gp has not yet been solved, there are now a handful of related structures on which homology models can be built to aid in the interpretation of the vast amount of experimental data that currently exists. Many models for P-gp have been built with this aim, but the situation is complicated by the apparent flexibility of the system and by the fact that although many potential templates exist, there is large variation in the conformational state in which they have been crystallized. In this review, we summarize how homology modelling has been used in the past, how models are typically selected and finally illustrate how MD simulations can be used as a means to give more confidence about models that have been generated via this approach.

Original publication




Journal article


Biochem Soc Trans

Publication Date





952 - 958


ATP-binding cassette (ABC) transporters, computational, export pump, molecular dynamics, multi-drug resistance, simulation, ATP Binding Cassette Transporter, Sub-Family B, Binding Sites, Biological Transport, Crystallography, X-Ray, Drug Resistance, Multiple, Humans, Lipid Bilayers, Molecular Dynamics Simulation, Pharmaceutical Preparations, Protein Conformation