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J. Biol. Chem., Vol. 277, Issue 7, 5008-5016, February 15, 2002
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§,
, and
From the The dynamic changes occurring during the
catalytic cycle of MDR3 P-glycoprotein (Pgp) and the role of
each nucleotide-binding domain (NBD) in the transport process were
investigated using attenuated total reflection Fourier transform
infrared spectroscopy. For this purpose, wild-type Pgp and two
mutations of homologous residues in each NBD 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 to the external environment. On the other
hand, amide H/D exchange kinetics demonstrate that homologous
mutations in the two NBDs affect, in a different way, the dynamic
properties of Pgp and also the dynamic changes occurring during ATP
hydrolysis. These observations led 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 decreased stability and/or
increased accessibility to the external medium of the membrane-embedded
drug-binding site(s). NBD1 would play an important role in this first
restructuring of the membrane-embedded domains. NBD2 would be
directly implicated in the subsequent restructuring of the
membrane-embedded binding sites by which they recover their initial
stability and accessibility to the membrane. It is proposed that this
restructuring step would allow the binding and transport of another
molecule of substrate.
Centre de Biologie Structurale et de
Bioinformatique, Université Libre de Bruxelles, B-1050 Brussels,
Belgium and the ¶ Department of Biochemistry, McGill University,
Montréal, Québec H3G 1Y6, Canada
Research Scholar of the Howard Hughes Medical Institute.
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