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

Producción científica: Article › revisión exhaustiva

13 Citas (SciVal)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	404-412.e4
Publicación	Structure
Volumen	29
N.º	5
DOI	https://doi.org/10.1016/j.str.2020.11.012
Estado	Published - may 6 2021

Nota bibliográfica

Publisher Copyright:
© 2020 Elsevier Ltd

Financiación

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.

Financiadores	Número del financiador
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

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Structural Biology
Molecular Biology

Acceder al documento

10.1016/j.str.2020.11.012

Otros archivos y enlaces

Citar esto

@article{d5e75710c85e4c229b23cc5480e22c64,

title = "Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins",

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",

author = "Caixia Hou and Abhisek Mandal and J{\"u}rgen Rohr and Tsodikov, \{Oleg V.\}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",

year = "2021",

month = may,

day = "6",

doi = "10.1016/j.str.2020.11.012",

language = "English",

volume = "29",

pages = "404--412.e4",

number = "5",

}

TY - JOUR

T1 - Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins

AU - Hou, Caixia

AU - Mandal, Abhisek

AU - Rohr, Jürgen

AU - Tsodikov, Oleg V.

PY - 2021/5/6

Y1 - 2021/5/6

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.

AB - 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.

KW - cancer

KW - crystal structure

KW - natural product

KW - protein-DNA binding

KW - transcription

UR - https://www.scopus.com/pages/publications/85097737985

UR - https://www.scopus.com/pages/publications/85097737985#tab=citedBy

U2 - 10.1016/j.str.2020.11.012

DO - 10.1016/j.str.2020.11.012

M3 - Article

C2 - 33275876

AN - SCOPUS:85097737985

SN - 0969-2126

VL - 29

SP - 404-412.e4

JO - Structure

JF - Structure

IS - 5

ER -

Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

Acceder al documento

Otros archivos y enlaces

Huella

Citar esto