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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Human small cell lung cancer NYH cells resistant to the bisdioxopiperazine ICRF-187 exhibit a functional dominant Tyr165Ser mutation in the Walker A ATP binding site of topoisomerase II alpha

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Bisdioxopiperazine anti-cancer agents are catalytic inhibitors of topoisomerase II which by unknown means lock the enzyme in a closed clamp form and inhibit its ATPase activity. In order to demarcate a putative pharmacophore, we here describe a novel Tyr165Ser mutation in the enzyme's Walker A ATP binding site leading to specific bisdioxopiperazine resistance when transformed into a temperature-conditional yeast system. The Tyr165Ser mutation differed from a previously described Arg162Gln by being heterozygous and by purified Tyr165Ser enzyme being drug-resistant in a kinetoplast DNA decatenation enzymatic assay. This suggested dominant nature of Tyr165Ser was supported by co-transformation studies in yeast of plasmids carrying wild type and mutant genes. These results enable a model of the bisdioxopiperazine pharmacophore using the proposed asymmetric ATP hydrolysis of the enzyme.

Original languageEnglish
JournalFEBS Letters
Volume520
Issue number1-3
Pages (from-to)161-6
Number of pages6
ISSN0014-5793
DOIs
Publication statusPublished - 5 Jun 2002

    Research areas

  • Adenosine Triphosphate/metabolism, Amino Acid Substitution, Antigens, Neoplasm, Antineoplastic Agents/pharmacology, Binding Sites/genetics, Carcinoma, Small Cell/enzymology, Cell Division/drug effects, DNA Topoisomerases, Type II/genetics, DNA-Binding Proteins, Dose-Response Relationship, Drug, Drug Resistance, Fungal/genetics, Drug Resistance, Neoplasm/genetics, Genotype, Humans, Lung Neoplasms/enzymology, Mutation, Protein Binding, Razoxane/pharmacology, Saccharomyces cerevisiae/drug effects, Transformation, Genetic, Tumor Cells, Cultured/drug effects

ID: 59178854