title: Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting.
abstract: Steroid hormone receptors (SHRs) act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator (SRM) ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain (LBD)/AF2 and neglect intrinsically disordered (ID) N-terminal domain (NTD)/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor's (AR's) ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR's structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer.
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D000970:Antineoplastic Agents; D064267:Intrinsically Disordered Proteins; D011944:Receptors, Androgen