Determinants of the substrate specificity of multidrug resistance protein 1: role of amino acid residues with hydrogen bonding potential in predicted transmembrane helix 17

The Journal of Biological Chemistry
Da-Wei ZhangRoger G Deeley

Abstract

Human multidrug resistance protein 1 (MRP1) confers resistance to many natural product chemotherapeutic agents and actively transports structurally diverse organic anion conjugates. We previously demonstrated that two hydrogen-bonding amino acid residues in the predicted transmembrane 17 (TM17) of MRP1, Thr(1242) and Trp(1246), were important for drug resistance and 17beta-estradiol 17-(beta-d-glucuronide) (E(2)17betaG) transport. To determine whether other residues with hydrogen bonding potential within TM17 influence substrate specificity, we replaced Ser(1233), Ser(1235), Ser(1237), Gln(1239), Thr(1241), and Asn(1245) with Ala and Tyr(1236) and Tyr(1243) with Phe. Mutations S1233A, S1235A, S1237A, and Q1239A had no effect on any substrate tested. In contrast, mutations Y1236F and T1241A decreased resistance to vincristine but not to VP-16, doxorubicin, and epirubicin. Mutation Y1243F reduced resistance to all drugs tested by 2-3-fold. Replacement of Asn(1245) with Ala also decreased resistance to VP-16, doxorubicin, and epirubicin but increased resistance to vincristine. This mutation also decreased E(2)17betaG transport approximately 5-fold. Only mutation Y1243F altered the ability of MRP1 to transport both leukotriene 4 an...Continue Reading

References

Jun 1, 1997·Seminars in Cancer Biology·R G Deeley, S P Cole
Jan 27, 1999·Biochimica Et Biophysica Acta·I T Arkin, A T Brunger
Jul 31, 1999·The Journal of Biological Chemistry·B D StrideR G Deeley
Dec 3, 1999·Biochimica Et Biophysica Acta·P BorstJ Wijnholds
Dec 3, 1999·Biochimica Et Biophysica Acta·D R HipfnerS P Cole
Mar 30, 2000·International Journal of Clinical Pharmacology and Therapeutics·A SeeligF Wohnsland
Jun 7, 2000·Proceedings of the National Academy of Sciences of the United States of America·J WijnholdsP Borst
Jul 13, 2000·The Journal of Biological Chemistry·G JedlitschkyD Keppler
Aug 17, 2000·Journal of the National Cancer Institute·P BorstJ Wijnholds
Sep 6, 2000·Trends in Biochemical Sciences·J A Killian, G von Heijne
Aug 11, 2001·Cellular and Molecular Life Sciences : CMLS·T LitmanS E Bates
Oct 3, 2001·The Journal of Biological Chemistry·N ZelcerP Borst
Nov 2, 2001·Biochemical and Biophysical Research Communications·H YabuuchiT Ishikawa
Dec 12, 2001·Science·M A SchumacherR G Brennan

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Citations

Jan 3, 2006·FEBS Letters·Roger G Deeley, Susan P C Cole
May 9, 2008·Drug Metabolism Reviews·Ulrike Gradhand, Richard B Kim
May 2, 2003·British Journal of Pharmacology·Xiao-Qin RenShin-ichi Akiyama
Oct 3, 2006·Biochimica Et Biophysica Acta·Valerie Gouaze-Andersson, Myles C Cabot
Oct 25, 2003·Oncogene·Gary D Kruh, Martin G Belinsky
Jan 31, 2006·FEBS Letters·Annie Frelet, Markus Klein
Jul 4, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Gwenaëlle ConseilSusan P C Cole
Jul 18, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kenichi NunoyaRoger G Deeley
Nov 9, 2002·The Journal of Biological Chemistry·Liliana ManciuJean Marie Ruysschaert
May 10, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Massoud SaidijamSimon G Patching
Dec 15, 2004·The Journal of Biological Chemistry·Xiaoyong BaoGuillermo A Altenberg
Jul 3, 2021·International Journal of Molecular Sciences·Flora SzeriKoen van de Wetering

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