How mithramycin stereochemistry dictates its structure and DNA binding function.

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

SUBMITTER: Hou C 

PROVIDER: S-EPMC6533888 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature