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Inhibition of DNA binding by human estrogen-related receptor 2 and estrogen receptor alpha with minor groove binding polyamides

Gearhart, Micah D. and Dickinson, Liliane and Ehley, Jennifer and Melander, Christian and Dervan, Peter B. and Wright, Peter E. and Gottesfeld, Joel M. (2005) Inhibition of DNA binding by human estrogen-related receptor 2 and estrogen receptor alpha with minor groove binding polyamides. Biochemistry, 44 (11). pp. 4196-4203. ISSN 0006-2960. https://resolver.caltech.edu/CaltechAUTHORS:20160509-110454000

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Abstract

Human estrogen-related receptor 2 (hERR2, ESRRB, ERRbeta, NR3B2) belongs to a class of nuclear receptors that bind DNA through sequence-specific interactions with a 5'-AGGTCA-3' estrogen response element (ERE) half-site in the major groove and an upstream 5'-TNA-3' site in the minor groove. This minor groove interaction is mediated by a C-terminal extension (CTE) of the DNA binding domain and is unique to the estrogen-related receptors. We have used synthetic pyrrole-imidazole polyamides, which bind specific sequences in the minor groove, to demonstrate that DNA binding by hERR2 is sensitive to the presence of polyamides in both the upstream minor groove CTE site and the minor groove of the ERE half-site. Thus, polyamides can inhibit hERR2 by two mechanisms, by direct steric blockage of minor groove DNA contacts mediated by the CTE and by changing the helical geometry of DNA such that major groove interactions are weakened. To confirm the generality of the latter approach, we show that the dimeric human estrogen receptor alpha (hERalpha, ESR1, NR3A1), which binds in the major groove of the ERE, can be inhibited by a polyamide bound in the opposing minor groove of the ERE. These results highlight two mechanisms for inhibition of protein-DNA interactions and extend the repertoire of DNA recognition motifs that can be inhibited by polyamides. These molecules may thus be useful for controlling expression of hERR2- or hERalpha-responsive genes.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/bi047872oDOIArticle
http://pubs.acs.org/doi/abs/10.1021/bi047872oPublisherArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2005 American Chemical Society. Received October 1, 2004; Revised Manuscript Received January 13, 2005. We thank Dr. Clara Kielkopf for advice and assistance with modeling studies.
Issue or Number:11
Record Number:CaltechAUTHORS:20160509-110454000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160509-110454000
Official Citation:Inhibition of DNA Binding by Human Estrogen-Related Receptor 2 and Estrogen Receptor α with Minor Groove Binding Polyamides Micah D. Gearhart, Liliane Dickinson, Jennifer Ehley, Christian Melander, Peter B. Dervan, Peter E. Wright, and Joel M. Gottesfeld Biochemistry 2005 44 (11), 4196-4203 DOI: 10.1021/bi047872o
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66758
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:17 May 2016 22:17
Last Modified:26 Nov 2019 11:15

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