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Proc. Natl. Acad. Sci. USA
Vol. 94,
pp. 12908-12913,
November 1997
* Department of Molecular Genetics, University of Illinois, Chicago,
IL 60607-7170;
Edited by Alexander Varshavsky, California Institute of
Technology, Pasadena, CA, and approved September 30, 1997 (received for review July 16, 1997)
The MDR1 P-glycoprotein (Pgp), a member of the ATP-binding
cassette family of transporters, is a transmembrane ATPase efflux pump
for various lipophilic compounds, including many anti-cancer drugs. mAb
UIC2, reactive with the extracellular moiety of Pgp, inhibits
Pgp-mediated efflux. UIC2 reactivity with Pgp was increased by the
addition of several Pgp-transported compounds or ATP-depleting agents,
and by mutational inactivation of both nucleotide-binding domains
(NBDs) of Pgp. UIC2 binding to Pgp mutated in both NBDs was unaffected
in the presence of Pgp transport substrates or in ATP-depleted cells,
whereas the reactivities of the wild-type Pgp and Pgps mutated in a
single NBD were increased by these treatments to the level of the
double mutant. These results indicate the existence of different Pgp
conformations associated with different stages of transport-associated
ATP hydrolysis and suggest trapping in a transient conformation as a
mechanism for antibody-mediated inhibition of Pgp.
Biochemistry
P-glycoprotein function involves conformational transitions
detectable by differential immunoreactivity
,
,,,
,, and Ingenex, Inc., Menlo Park, CA 94025;
Oncotech, Inc., Irvine, CA 92614; Department of
Biological Chemistry, Hebrew University, Jerusalem 91904, Israel;
** Becton Dickinson Immunocytometry Systems, San Jose, CA 95131; and
Institute of Molecular and Cellular Biosciences,
University of Tokyo, Tokyo 113, Japan
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