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 language | English |
|---|---|
| Pages (from-to) | 404-412.e4 |
| Journal | Structure |
| Volume | 29 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 6 2021 |
Bibliographical note
Publisher Copyright:© 2020 Elsevier Ltd
Funding
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.
| Funders | Funder number |
|---|---|
| Center for Structural Biology | |
| National Institutes of Health (NIH) | |
| U.S. Department of Defense | PC150300 |
| National Childhood Cancer Registry – National Cancer Institute | R01CA243529 |
| University of Kentucky |
Keywords
- cancer
- crystal structure
- natural product
- protein-DNA binding
- transcription
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology
