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Mutational Analysis of Conserved Carboxylate Residues in the Nucleotide Binding Sites of P-Glycoprotein

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Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6
Cite this: Biochemistry 2000, 39, 46, 14138–14149
Publication Date (Web):October 24, 2000
Copyright © 2000 American Chemical Society

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    Mutagenesis was used to investigate the functional role of six pairs of aspartate and glutamate residues (D450/D1093, E482/E1125, E552/E1197, D558/D1203, D592/D1237, and E604/E1249) that are highly conserved in the nucleotide binding sites of P-glycoprotein (Mdr3) and of other ABC transporters. Removal of the charge in E552Q/E1197Q and D558N/D1203N produced proteins with severely impaired biological activity when the proteins were analyzed in yeast cells for cellular resistance to FK506 and restoration of mating in a ste6Δ mutant. Mutations at other acidic residues had no apparent effect in the same assays. These four mutants were expressed in Pichia pastoris, purified to homogeneity, and biochemically characterized with respect to ATPase activity. Studies with purified proteins showed that mutants D558N and D1203N retained 14 and 30% of the drug-stimulated ATPase activity of wild-type (WT) Mdr3, respectively, and vanadate trapping of 8-azido[α-32P]nucleotide confirmed slower basal and drug-stimulated 8-azido-ATP hydrolysis compared to that for WT Mdr3. The E552Q and E1197Q mutants showed no drug-stimulated ATPase activity. Surprisingly, drugs did stimulate vanadate trapping of 8-azido[α-32P]nucleotide in E552Q and E1197Q at a level similar to that of WT Mdr3. This suggests that formation of the catalytic transition state can occur in these mutants, and that the bond between the β- and γ-phosphates is hydrolyzed. In addition, photolabeling by 8-azido[α-32P]nucleotide in the presence or absence of drug was also detected in the absence of vanadate in these mutants. These results suggest that steps after the transition state, possibly involved in release of MgADP, are severely impaired in these mutant enzymes.

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     This work was supported by research grants to P.G. from the Medical Research Council (MRC) of Canada. P.G. is an International Research Scholar of the Howard Hughes Medical Institute and is a Career Scientist of the MRC of Canada.

     These authors have contributed equally to this work.


     To whom all correspondence should be addressed:  Department of Biochemistry, McGill University, 3655 Drummond, Room 907, Montréal, Québec, Canada H3G 1Y6. Phone:  (514) 398-7291. Fax:  (514) 398-2603. E-mail:  [email protected].

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    Multiple sequence alignments containing 270 sequences for NB1 and 322 sequences for NB2 or their equivalents in ABC transporters. This material is available free of charge via the Internet at

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