%0 Journal Article
%T Molecular models of human P-glycoprotein in two different catalytic states
%A Jean-Paul Becker
%A Gr¨¦goire Depret
%A Fran£¿oise Van Bambeke
%A Paul M Tulkens
%A Martine Pr¨¦vost
%J BMC Structural Biology
%D 2009
%I BioMed Central
%R 10.1186/1472-6807-9-3
%X We present here three-dimensional models of two different catalytic states of P-glycoprotein that were developed based on the crystal structures of two bacterial multidrug transporters. Our models are supported by a large body of biochemical data. Measured inter-residue distances correlate well with distances derived from cross-linking data. The nucleotide-free model features a large cavity detected in the protein core into which ligands of different size were successfully docked. The locations of docked ligands compare favorably with those suggested by drug binding site mutants.Our models can interpret the effects of several mutants in the nucleotide-binding domains (NBDs), within the transmembrane domains (TMDs) or at the NBD:TMD interface. The docking results suggest that the protein has multiple binding sites in agreement with experimental evidence. The nucleotide-bound models are exploited to propose different pathways of signal transmission upon ATP binding/hydrolysis which could lead to the elaboration of conformational changes needed for substrate translocation. We identified a cluster of aromatic residues located at the interface between the NBD and the TMD in opposite halves of the molecule which may contribute to this signal transmission.Our models may characterize different steps in the catalytic cycle and may be important tools to understand the structure-function relationship of P-glycoprotein.ATP-binding cassette (ABC) proteins form a large protein family in living organisms that carry various substrates across cell membranes. There are 48 ABC transporters in humans and mutations in many have been linked to genetic disorders[1,2].The P-glycoprotein (P-gp), product of the mdr1 gene in humans, is one of these ABC transporters that extrudes a large range of structurally diverse compounds out of cells, a feature that has been described as poly-specificity[3,4]. It is the most extensively studied ABC transporter and can be used to understand the function o
%U http://www.biomedcentral.com/1472-6807/9/3