1: BMC Struct Biol. 2009 Jan 22;9:3.

Molecular models of human P-glycoprotein in two different catalytic states.

Becker JP, Depret G, Van Bambeke F, Tulkens PM, Prévost M.

Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles,
Boulevard du Triomphe CP 206/2, B-1050 Brussels, Belgium. jpbecker@ulb.ac.be

BACKGROUND: P-glycoprotein belongs to the family of ATP-binding cassette proteins
which hydrolyze ATP to catalyse the translocation of their substrates through
membranes. This protein extrudes a large range of components out of cells,
especially therapeutic agents causing a phenomenon known as multidrug resistance.
Because of its clinical interest, its activity and transport function have been
largely characterized by various biochemical studies. In the absence of a
high-resolution structure of P-glycoprotein, homology modeling is a useful tool
to help interpretation of experimental data and potentially guide experimental
studies. RESULTS: 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. CONCLUSION: 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.

PMCID: PMC2661087
PMID: 19159494 [PubMed - in process]

Related Links

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