甾体激素受体的变构调节剂:结构动力学与基因调控。
Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation.
机构信息
Department of Basic Sciences, The Commonwealth Medical College, Scranton, Pennsylvania 18510, USA.
出版信息
Endocr Rev. 2012 Apr;33(2):271-99. doi: 10.1210/er.2011-1033. Epub 2012 Mar 20.
Steroid hormones are synthesized from cholesterol primarily in the adrenal gland and the gonads and play vital roles in normal physiology, the control of development, differentiation, metabolic homeostasis, and reproduction. The actions of these small lipophilic molecules are mediated by intracellular receptor proteins. It is just over 25 yr since the first cDNA for steroid receptors were cloned, a development that led to the birth of a superfamily of ligand-activated transcription factors: the nuclear receptors. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains but possess distinct N-terminal domains and hinge regions that are intrinsically disordered. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action, and biology of this important class of ligand-activated transcription factors. In recent years, there has been interest in the structural plasticity and function of the N-terminal domain of steroid hormone receptors and in the allosteric regulation of protein folding and function in response to hormone, DNA response element architecture, and coregulatory protein binding partners. The N-terminal domain can exist as an ensemble of conformers, having more or less structure, which prime this region of the receptor to rapidly respond to changes in the intracellular environment through hormone binding and posttranslation modifications. In this review, we address the question of receptor structure and function dynamics with particular emphasis on the structurally flexible N-terminal domain, intra- and interdomain communications, and the allosteric regulation of receptor action.
甾体激素主要在肾上腺和性腺中从胆固醇合成,在正常生理、发育控制、分化、代谢稳态和生殖中发挥重要作用。这些小疏水分子的作用是通过细胞内受体蛋白介导的。自从首次克隆甾体受体的 cDNA 以来,已经过去了 25 年多,这一发展导致了配体激活转录因子的超级家族的诞生:核受体。受体蛋白在结构和功能上具有相关的配体结合和 DNA 结合结构域,但具有独特的 N 端结构域和铰链区,这些结构域是固有无序的。自最初的克隆实验以来,我们对这类重要的配体激活转录因子的结构、作用机制和生物学特性的理解取得了相当大的进展。近年来,人们对甾体激素受体 N 端结构域的结构可塑性和功能以及对蛋白质折叠和功能的变构调节(响应激素、DNA 反应元件结构和共调节蛋白结合伴侣)产生了兴趣。N 端结构域可以作为构象的集合体存在,具有或多或少的结构,使受体的这一区域能够通过激素结合和翻译后修饰,快速响应细胞内环境的变化。在这篇综述中,我们特别强调结构灵活的 N 端结构域、域内和域间通讯以及受体作用的变构调节,来探讨受体结构和功能动态的问题。