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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines
Nucleic Acids Research, Volume 42, No. 2, Year 2014
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Description
ETS transcription factors mediate a wide array of cellular functions and are attractive targets for pharmacological control of gene regulation. We report the inhibition of the ETS-family member PU.1 with a panel of novel heterocyclic diamidines. These diamidines are derivatives of furamidine (DB75) in which the central furan has been replaced with selenophene and/or one or both of the bridging phenyl has been replaced with benzimidazole. Like all ETS proteins, PU.1 binds sequence specifically to 10-bp sites by inserting a recognition helix into the major groove of a 5′-GGAA-3′ consensus, accompanied by contacts with the flanking minor groove. We showed that diamidines target the minor groove of AT-rich sequences on one or both sides of the consensus and disrupt PU.1 binding. Although all of the diamidines bind to one or both of the expected sequences within the binding site, considerable heterogeneity exists in terms of stoichiometry, site-site interactions and induced DNA conformation. We also showed that these compounds accumulate in live cell nuclei and inhibit PU.1-dependent gene transactivation. This study demonstrates that heterocyclic diamidines are capable of inhibiting PU.1 by targeting the flanking sequences and supports future efforts to develop agents for inhibiting specific members of the ETS family. © 2013 The Author(s).
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3902942/bin/supp_42_2_1379__index.html
https://efashare.b-cdn.net/share/pmc/articles/PMC3902942/bin/supp_gkt955_nar-01942-f-2013-File008.pdf
Authors & Co-Authors
Munde, Manoj M.
United States, Atlanta
Georgia State University
Kumar, Arvind
United States, Atlanta
Georgia State University
Stephens, Chad E.
United States, Atlanta
Georgia State University
Farahat, Abdelbasset A.
United States, Atlanta
Georgia State University
Boykin, David Withers
United States, Atlanta
Georgia State University
Wilson, W. David
United States, Atlanta
Georgia State University
Poon, Gregory M.K.
United States, Pullman
Washington State University Pullman
Statistics
Citations: 53
Authors: 7
Affiliations: 2
Identifiers
Doi:
10.1093/nar/gkt955
ISSN:
03051048
Research Areas
Genetics And Genomics