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Research ArticleArticle

MUTATIONAL ANALYSIS OF POLAR AMINO ACID RESIDUES WITHIN PREDICTED TRANSMEMBRANE HELICES 10 AND 16 OF MULTIDRUG RESISTANCE PROTEIN 1 (ABCC1): EFFECT ON SUBSTRATE SPECIFICITY

Da-Wei Zhang, Kenichi Nunoya, Monika Vasa, Hong-Mei Gu, Susan P. C. Cole and Roger G. Deeley
Drug Metabolism and Disposition April 2006, 34 (4) 539-546; DOI: https://doi.org/10.1124/dmd.105.007740
Da-Wei Zhang
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Kenichi Nunoya
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Monika Vasa
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Hong-Mei Gu
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Susan P. C. Cole
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Roger G. Deeley
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Abstract

Human multidrug resistance protein 1 (MRP1) has a total of 17 transmembrane (TM) helices arranged in three membrane-spanning domains, MSD0, MSD1, and MSD2, with a 5 + 6 + 6 TM configuration. Photolabeling studies indicate that TMs 10 and 11 in MSD1 and 16 and 17 in MSD2 contribute to the substrate binding pocket of the protein. Previous mutational analyses of charged and polar amino acids in predicted TM helices 11, 16, and 17 support this suggestion. Mutation of Trp553 in TM10 also affects substrate specificity. To extend this analysis, we mutated six additional polar residues within TM10 and the remaining uncharacterized polar residue in TM16, Asn1208. Although mutation of Asn1208 was without effect, two of six mutations in TM10, T550A and T556A, modulated the drug resistance profile of MRP1 without affecting transport of leukotriene C4, 17β-estradiol 17-(β-d-glucuronide) (E217βG), and glutathione. Mutation T550A increased vincristine resistance but decreased doxorubicin resistance, whereas mutation T556A decreased resistance to etoposide (VP-16) and doxorubicin. Although conservative mutation of Tyr568 in TM10 to Phe or Trp had no apparent effect on substrate specificity, substitution with Ala decreased the affinity of MRP1 for E217βG without affecting drug resistance or the transport of other substrates tested. These analyses confirm that several amino acids in TM10 selectively alter the substrate specificity of MRP1, suggesting that they interact directly with certain substrates. The location of these and other functionally important residues in TM helices 11, 16, and 17 is discussed in the context of an energy-minimized model of the membrane-spanning domains of MRP1.

Footnotes

  • This work was supported by a grant from the National Cancer Institute of Canada with funds from the Terry Fox Run.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.007740.

  • ABBREVIATIONS: MRP, multidrug resistance protein; ABC, ATP-binding cassette transporter; MSD, membrane-spanning domain; TM, transmembrane; mAb, monoclonal antibody; E217βG, 17β-estradiol 17-(β-d-glucuronide); GSH, glutathione; LTC4, leukotriene C4; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; VP-16, etoposide; HEK, human embryonic kidney; PBS, phosphate-buffered saline.

  • ↵1 Current affiliation: Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

  • ↵2 Current affiliation: Department of Xenobiotic Metabolism and Disposition, Minase Research Institute, Ono Pharmaceutical Co., Ltd, Osaka, Japan.

    • Received November 7, 2005.
    • Accepted January 12, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (4)
Drug Metabolism and Disposition
Vol. 34, Issue 4
1 Apr 2006
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Research ArticleArticle

MUTATIONAL ANALYSIS OF POLAR AMINO ACID RESIDUES WITHIN PREDICTED TRANSMEMBRANE HELICES 10 AND 16 OF MULTIDRUG RESISTANCE PROTEIN 1 (ABCC1): EFFECT ON SUBSTRATE SPECIFICITY

Da-Wei Zhang, Kenichi Nunoya, Monika Vasa, Hong-Mei Gu, Susan P. C. Cole and Roger G. Deeley
Drug Metabolism and Disposition April 1, 2006, 34 (4) 539-546; DOI: https://doi.org/10.1124/dmd.105.007740

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Research ArticleArticle

MUTATIONAL ANALYSIS OF POLAR AMINO ACID RESIDUES WITHIN PREDICTED TRANSMEMBRANE HELICES 10 AND 16 OF MULTIDRUG RESISTANCE PROTEIN 1 (ABCC1): EFFECT ON SUBSTRATE SPECIFICITY

Da-Wei Zhang, Kenichi Nunoya, Monika Vasa, Hong-Mei Gu, Susan P. C. Cole and Roger G. Deeley
Drug Metabolism and Disposition April 1, 2006, 34 (4) 539-546; DOI: https://doi.org/10.1124/dmd.105.007740
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