Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins

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

doi:10.1016/j.str.2020.11.012

Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins

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

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	404-412.e4
Journal	Structure
Volume	29
Issue number	5
DOIs	https://doi.org/10.1016/j.str.2020.11.012
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.str.2020.11.012

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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.",

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N2 - 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.

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Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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