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

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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