Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins

Caixia Hou, Abhisek Mandal, Jürgen Rohr, Oleg V. Tsodikov

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

ETS family transcription factors of ERG and FLI1 play a key role in oncogenesis of prostate cancer and Ewing sarcoma by binding regulatory DNA sites and interfering with function of other factors. Mithramycin (MTM) is an anti-cancer, DNA binding natural product that functions as a potent antagonist of ERG and FLI1 by an unknown mechanism. We present a series of crystal structures of the DNA binding domain (DBD) of ERG/FLI1 culminating in a structure of a high-order complex of the ERG/FLI1 DBD, transcription factor Runx2, core-binding factor beta (Cbfβ), and MTM on a DNA enhancer site, along with supporting DNA binding studies using MTM and its analogues. Taken together, these data provide insight into allosteric mechanisms underlying ERG and FLI1 transactions and their disruption by MTM analogues.

Original languageEnglish
Pages (from-to)404-412.e4
JournalStructure
Volume29
Issue number5
DOIs
StatePublished - May 6 2021

Bibliographical note

Funding Information:
We thank Dr. Anne George for providing the runx2 vector for subcloning, the staff of sector 22 of the Advanced Photon Source at Argonne National Laboratory for assistance with remote data collection, and Dr. Mark Leggas for discussing this work. This work was supported by the U.S. Department of Defense grant no. PC150300 and NIH grant R01CA243529 to O.V.T. and J.R. Access to the synchrotron was supported by the Center for Structural Biology at the University of Kentucky.

Publisher Copyright:
© 2020 Elsevier Ltd

Keywords

  • cancer
  • crystal structure
  • natural product
  • protein-DNA binding
  • transcription

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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