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Capturing transient transcriptional activator‐coactivator complexes with large and small molecules
Author(s) -
Mapp Anna K
Publication year - 2013
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.27.1_supplement.459.2
Subject(s) - coactivator , activator (genetics) , transcription (linguistics) , small molecule , rna polymerase , rna polymerase ii , polymerase , promoter , biology , transcription factor , computational biology , enzyme , microbiology and biotechnology , chemistry , gene , biophysics , rna , genetics , gene expression , biochemistry , linguistics , philosophy
Most essential cellular functions are accomplished by dynamic macromolecular assemblies comprised of least one enzyme component surrounded by non‐enzymatic moieties that enforce the timing, location and specificity of the complex function. In the case of transcription, transcriptional activators direct the assembly of the RNA polymerase II holoenzyme at specific gene promoters at particular time points; once the polymerase is engaged, the complex disassembles as transcription initiates. This is accomplished through protein‐protein interactions (PPIs) that are dynamic and, in some cases, short‐lived. Despite their prevalence and functional importance, these PPIs are historically all but impossible for small molecule modulation and are typically classified as ‘undruggable’. The challenge is multi‐variable: the binding partners often have significant disorder and are thus difficult to characterize structurally alone or in complex; the surface area of the area of the interactions are considerably larger than protein‐ligand interactions, and the strengths of the interactions are modest. Two distinct classes of modulators of coactivator‐activator complexes will be discussed, with applications in the covalent capture and characterization of the complexes as well as modulation of assemblies in the context of head and neck squamous cell carcinoma.