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How mithramycin stereochemistry dictates its structure and DNA binding function

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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.

Graphical abstract: How mithramycin stereochemistry dictates its structure and DNA binding function

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Publication details

The article was received on 19 Feb 2019, accepted on 28 Mar 2019 and first published on 28 Mar 2019


Article type: Research Article
DOI: 10.1039/C9MD00100J
Citation: Med. Chem. Commun., 2019, Advance Article

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    How mithramycin stereochemistry dictates its structure and DNA binding function

    C. Hou, J. Rohr, S. Parkin and O. V. Tsodikov, Med. Chem. Commun., 2019, Advance Article , DOI: 10.1039/C9MD00100J

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