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Updated: Jan 23, 2026

A Protocol for Computer-Based Protein Structure and Function Prediction
Published on: November 3, 2011
How mithramycin stereochemistry dictates its structure and DNA binding function
Caixia Hou1, Jürgen Rohr1, Sean Parkin2
1University of Kentucky , Department of Pharmaceutical Sciences , College of Pharmacy , Lexington , KY 40536-0596 , USA . Email: oleg.tsodikov@uky.edu ;
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.
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