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Vol. 56, Issue 5, 997-1004, November 1999
Laboratories of Molecular Biology (Y.Z., I.P.) and Cell Biology
(M.M.G.), National Cancer Institute, National Institutes of Health,
Bethesda, Maryland
Multidrug resistance (MDR) mediated by P-glycoprotein (MDR1) is
clinically significant. Understanding how MDR1 substrate specificity is
determined will help to overcome MDR to improve cancer treatment. One
potential approach to achieve this goal is to study chimeras of MDR1
and its homolog MDR2 (also called MDR3), which has been identified as a
phosphatidylcholine flippase. With an approach involving exchanging
homologous segments of MDR1 and MDR2 and site-directed mutagenesis, we
previously demonstrated MDR1 residues Q330, V331, and L332 in
transmembrane domain 6 (TM6) are essential for multidrug transport
activity; substituting these residues allows the N-terminal
transmembrane region of MDR2 to support MDR1 activity. To further
determine the exchangeability between MDR1 and MDR2, we constructed
additional MDR1/MDR2 chimeras. We found that the N-terminal half of
MDR1 and MDR2 was mostly exchangeable except for a few residues in TM6.
However, this degree of exchangeability was not found in the C-terminal
half of MDR1 and MDR2. In addition, with substitution of MDR1 residues
318-332 (TM6) and 937-994 (TM11-12), MDR2 had relatively normal
affinity for MDR1 substrates, but it did not have multidrug transporter
activity. These results suggest that the inability of MDR2 to transport
most MDR1 drugs efficiently may be due to failure of those drugs to
stimulate ATPase and activate transport as well as to decreased drug binding.
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