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Papers In Press, published online ahead of print December 10, 2001
Centre de Biologie Structurale et de Bioinformatique, Université Libre de Bruxelles, Brussels 1050
Corresponding Author: cvigano{at}ulb.ac.be
The dynamical changes occurring during the catalytic cycle of Mdr3 P-glycoprotein (Pgp) and the role of each Nucleotide Binding Domains (NBD) in the transport process were investigated using Attenuated Total Reflection Fourier Transform Infrared spectroscopy (ATR-FTIR). For that purpose, Pgp wild type (WT) and two mutants in homologous residues of each NBDs were studied. On the one hand, we demonstrate here that during its catalytic cycle, Pgp does not undergo secondary structure changes but only modifications in its stability and accessibility towards the external environment. On the other hand, H/D exchange kinetics demonstrate that homologous mutations in the two NBDs affect in a different way the dynamical properties of Pgp and also the dynamical changes occurring during ATP hydrolysis. These observations lead to the conclusion that the NBDs have an asymmetric structure and different functions in the catalytic cycle of Pgp. Our data suggest that the release of drug from the membrane into the extracellular environment is due to a decreased stability and/or increased accessibility towards the external medium of the membrane-embedded drug binding site(s). NBD1 would play an important role in this first restructuration of the membrane-embedded domains. NBD2 would be directly implicated in a subsequent restructuration of the membrane-embedded binding sites by which they recover their initial stability and accessibility towards the membrane. It is proposed that this restructuration step would allow the binding and transport of another molecule of substrate.
J. Biol. Chem, 10.1074/jbc.M107928200
Submitted on August 17, 2001
Revised on December 7, 2001
Accepted on December 10, 2001
Structural and functional asymmetry of the nucleotide binding domains of P-glycoprotein investigated by attenuated total reflection fourier transform infrared spectroscopy
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