Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins

Structure. 2021 May 6;29(5):404-412.e4. doi: 10.1016/j.str.2020.11.012. Epub 2020 Dec 3.

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.

Keywords: cancer; crystal structure; natural product; protein-DNA binding; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Regulation / drug effects
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacology*
  • Binding Sites
  • Core Binding Factor Alpha 1 Subunit / chemistry
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Core Binding Factor beta Subunit / chemistry
  • Core Binding Factor beta Subunit / metabolism
  • Humans
  • Molecular Docking Simulation
  • Plicamycin / chemistry
  • Plicamycin / pharmacology*
  • Protein Binding
  • Proto-Oncogene Protein c-fli-1 / chemistry*
  • Proto-Oncogene Protein c-fli-1 / metabolism
  • Transcriptional Regulator ERG / chemistry
  • Transcriptional Regulator ERG / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Core Binding Factor Alpha 1 Subunit
  • Core Binding Factor beta Subunit
  • ERG protein, human
  • FLI1 protein, human
  • Proto-Oncogene Protein c-fli-1
  • RUNX2 protein, human
  • Transcriptional Regulator ERG
  • Plicamycin