Gronemeyer H, Miturski R
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, Illkirch, France.
Cell Mol Biol Lett. 2001;6(1):3-52.
In the past few years our understanding of nuclear receptor (NR) action has been dramatically improved. This is due to to advancements in three fields, (i) 3D structure determination, (ii) analysis of the complexes formed between nuclear receptors and co-regulatory molecules, and (iii) the genetic analysis of nuclear receptor signalling by gene "knock out" and "knock in" technologies. The elucidation of the crystal structure of apo-, holo (agonist)- and antagonist-NR ligand-binding domain (LBD) complexes is of outstanding importance for our understanding of the structural principles, in particular of the ligand-induced allosteric alterations, that are at the basis of receptor action. The concomitant identification and functional analysis of co-regulators (TIFs, coactivators and co-repressors) previously predicted from squelching studies have provided the possibility to understand the propagation of the original signal from ligand binding through intramolecular allosteric effects to intermolecular interactions. Recent crystal data of receptor LBD heterodimers and LBD-agonist complexes with nuclear receptor interacting peptides of co-activators have provided molecular insights into receptor dimerization and receptor-coactivator interaction. Finally, analysis of the signalling compexes established over nuclear receptors, assembling enzymatic activities that can alter the acetylation status of chromatin at the promoter regions of target genes and (de)acetylate other transcription regulatory factors paves the way to a comprehension of receptor action at the chromatin level. But much remains to be learnt and the recent studies have pointed towards an enormous complexity of this signalling system. Insights into the mechanistic basis of promyelocytic leukemia and the role of retinoic acid in differentiation therapy have been obtained as a consequence of the above studies, justified the efforts and led to an increasing awareness of the nuclear receptor signalling systems in basic and applied research. Here we will review recent data with the focus on what we have learnt about the interplay between NR structure and function to provide a view of the early steps of nuclear receptor action.
在过去几年中，我们对核受体（NR）作用的理解有了显著提升。这得益于三个领域的进展：（i）三维结构测定；（ii）核受体与共调节分子形成的复合物分析；（iii）通过基因“敲除”和“敲入”技术对核受体信号传导进行的遗传学分析。载脂蛋白、全（激动剂）和拮抗剂 - NR配体结合域（LBD）复合物晶体结构的阐明，对于我们理解受体作用基础的结构原理，特别是配体诱导的变构变化，具有极其重要的意义。先前通过抑制研究预测的共调节因子（TIFs、共激活剂和共抑制剂）的同时鉴定和功能分析，为理解从配体结合开始，通过分子内变构效应到分子间相互作用的原始信号传播提供了可能。受体LBD异二聚体以及LBD - 激动剂与共激活剂的核受体相互作用肽复合物的最新晶体数据，为受体二聚化和受体 - 共激活剂相互作用提供了分子层面的见解。最后，对核受体上建立的信号复合物的分析，这些复合物集合了可改变靶基因启动子区域染色质乙酰化状态以及使其他转录调节因子（去）乙酰化的酶活性，为在染色质水平理解受体作用铺平了道路。但仍有许多有待学习的内容，最近的研究表明这个信号系统极其复杂。上述研究获得了对早幼粒细胞白血病机制基础以及视黄酸在分化治疗中作用的见解，证明了这些努力的合理性，并使基础研究和应用研究中对核受体信号系统的认识不断提高。在此，我们将回顾近期数据，重点关注我们对NR结构与功能之间相互作用的了解，以呈现核受体作用早期步骤的概况。
