title: Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges.
abstract: Therapeutic targeting of nuclear receptors (NRs) is presently restricted due to 2 constraints: 1) a limited knowledge of the structural dynamics of intact receptor when complexed to DNA and coregulatory proteins; and 2) the inability to more selectively modulate NR actions at specific organ/gene targets. A major obstacle has been the current lack of understanding about the function and structure of the intrinsically disordered N-terminal domain that contains a major regulatory transcriptional activation function (AF1). Current studies of both mechanism of action and small molecule-selective receptor modulators for clinical uses target the structured pocket of the ligand-binding domain to modulate coregulatory protein interactions with the other activation function AF2. However, these approaches overlook AF1 activity. Recent studies have shown that highly flexible intrinsically disordered regions of transcription factors, including that of the N-terminal domain AF1 of NRs, not only are critical for several aspects of NR action but also can be exploited as drug targets, thereby opening unique opportunities for endocrine-based therapies. In this review article, we discuss the role of structural flexibilities in the allosteric modulation of NR activity and future perspectives for therapeutic interventions.
authors.affiliation: Steroid Hormones Section (S.S.S.), Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Departments of Molecular & Cellular Biology and Pathology & Immunology (D.P.E.), Baylor College of Medicine, Houston, Texas 77030; and Department of Basic Sciences (R.K.), The Commonwealth Medical College, Scranton, Pennsylvania 18510.
authors.forename: S Stoney
authors.initials: SS
authors.lastname: Simons
authors.forename: Dean P
authors.initials: DP
authors.lastname: Edwards
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000502:physiology; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D064267:Intrinsically Disordered Proteins; D018160:Receptors, Cytoplasmic and Nuclear