How mithramycin stereochemistry dictates its structure and DNA binding function

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8 Scopus citations

Abstract

An aureolic acid natural product mithramycin (MTM) has been known for its potent antineoplastic properties. MTM inhibits cell growth by binding in the minor groove of double-stranded DNA as a dimer, in which the two molecules of MTM are coordinated to each other through a divalent metal ion. A crystal structure of an MTM analogue, MTM SA-Phe, in the active metal ion-coordinated dimeric form demonstrates how the stereochemical features of MTM define the helicity of the dimeric scaffold for its binding to a right-handed DNA double helix. We also show crystallographically and biochemically that MTM, but not MTM SA-Phe, can be inactivated by boric acid through formation of a large macrocyclic species, in which two molecules of MTM are crosslinked to each other through 3-side chain-boron-sugar intermolecular bonds. We discuss these structural and biochemical properties in the context of MTM biosynthesis and the design of MTM analogues as anticancer therapeutics.

Original languageEnglish
Pages (from-to)735-741
Number of pages7
JournalMedChemComm
Volume10
Issue number5
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
This work was supported by US Department of Defense grant PC150300P1 to O. V. T. and J. R., by National Institutes of Health grant CA091901 to J. R. and by National Science Foundation MRI grants CHE-0319176 and CHE-1625732 to S. P. and O. V. T.

Publisher Copyright:
© 2019 The Royal Society of Chemistry.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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