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Intrinsically disordered N‐terminal domain of the steroid receptors: a promising target for endocrine‐based therapeutics (977.1)
Author(s) -
Kumar Raj,
Khan Shagufta
Publication year - 2014
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.28.1_supplement.977.1
Subject(s) - receptor , microbiology and biotechnology , chemistry , glucocorticoid receptor , computational biology , small molecule , nuclear receptor , gene , biology , biophysics , biochemistry , transcription factor
Organ/gene‐specific therapeutic targeting of steroid receptors (SRs) is presently restricted due, in part, to small molecule selective receptor modulators (SRMs) mainly targeting the structured pocket of the ligand binding domain to modulate co‐regulatory protein interactions with the AF2 and largely overlooking AF1 activity, located in the intrinsically disordered (ID) N‐terminal domain, which is a major contributor to cell/tissue and target gene specific actions of SRMs. It thus is axiomatic that attempts to more precisely control SR selectivity without understanding the actions of AF1 will be of limited success. A major challenge is the paucity of information on how and what kind of disorder‐order transition ID AF1 undergoes that leads to its functionally active folded conformation. In this study, we showed that the binding of glucocorticoid receptor’s ID AF1 to a target protein, as assessed by surface plasmon resonance (BIACORE), results into AF1 undergoing a disorder‐to‐order transition as determined by biophysical and proteomic techniques. Additionally, this induced folding of the AF1 is associated with enhancement of AF1‐mediated specific SR coactivators binding and subsequent transcriptional activity in vitro as determined by immunoprecipitation and promoter‐reporter assays. Targeting ID regions with small molecule drugs that can inhibit protein‐protein interactions at disorder‐to‐order transition is an emerging field with excellent promise; therefore, our results may provide additional SR selectivity needed to target cell‐tissue specific gene regulations in current endocrine‐based therapies.