Dimerization and DNA recognition rules of mithramycin and its analogues

Stevi Weidenbach, Caixia Hou, Jhong Min Chen, Oleg V. Tsodikov, Jürgen Rohr

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me2 +)-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM = MTM SDK > MTM SA-Trp > MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents.

Original languageEnglish
Pages (from-to)40-47
Number of pages8
JournalJournal of Inorganic Biochemistry
Volume156
DOIs
StatePublished - Mar 1 2016

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health CA091901 and GM105977 (to J.R.) and by a Markey Cancer Center Pilot Award.

Publisher Copyright:
© 2015 Published by Elsevier Inc.

Keywords

  • Anticancer agent
  • DNA binding
  • Metal ion coordination
  • Minor groove
  • Natural product

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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