Simons S Stoney, Edwards Dean P, Kumar Raj
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.
Mol Endocrinol. 2014 Feb;28(2):173-82. doi: 10.1210/me.2013-1334. Epub 2013 Nov 27.
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.
目前，由于两个限制因素，核受体（NRs）的治疗靶向受到限制：1）对完整受体与DNA和共调节蛋白复合时的结构动力学了解有限；2）无法更有选择性地调节NR在特定器官/基因靶点的作用。一个主要障碍是目前对包含主要调节转录激活功能（AF1）的内在无序N端结构域的功能和结构缺乏了解。目前关于临床应用的作用机制和小分子选择性受体调节剂的研究都针对配体结合结构域的结构化口袋，以调节共调节蛋白与另一个激活功能AF2的相互作用。然而，这些方法忽略了AF1的活性。最近的研究表明，转录因子的高度灵活的内在无序区域，包括NRs的N端结构域AF1，不仅对NR作用的几个方面至关重要，而且可以作为药物靶点加以利用，从而为基于内分泌的治疗开辟了独特的机会。在这篇综述文章中，我们讨论了结构灵活性在NR活性变构调节中的作用以及治疗干预的未来前景。
