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Dissecting protein complexes with small molecules
Author(s) -
Mapp Anna K
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.411.1
Subject(s) - transcriptional regulation , small molecule , function (biology) , computational biology , microbiology and biotechnology , transcriptional activity , biology , chemistry , biochemistry , gene , transcription factor
Altered transcriptional patterns are associated with all human diseases, either as a cause of the disease or as an effect. For this reason, molecules that interfere with or promote protein‐protein interactions within the transcriptional regulatory network are attractive targets for therapeutic development and as mechanistic probes. Despite the complexity of the transcriptional regulatory system, the design principles for the identification of small molecules that stimulate assembly of the transcriptional machinery complex are evidently straightforward. We find that several structurally distinct amphipathic molecular scaffolds can function in vitro and in human cells as transcriptional activation domains. In addition, structural studies of these molecules in complex with transcriptional machinery proteins reveal that they target the binding surfaces used by natural transcriptional activators and do so with similar affinity and kinetic profile. Finally, straightforward structural modifications of the molecules can be used to convert them into potent inhibitors of transcriptional machinery assembly. Financial support was provided by the American Cancer Society (RSG 05‐195‐01), the NSF, GSK and Novartis.