Shao G, Heyman R A, Schulman I G
Nuclear Receptor Discovery, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA.
Mol Endocrinol. 2000 Aug;14(8):1198-209. doi: 10.1210/mend.14.8.0495.
Binding of agonists to nuclear receptors results in a conformational change in receptor structure that promotes interaction between activated receptors and coactivators. Receptor-coactivator interactions are mediated by the agonist-dependent formation of a hydrophobic pocket on the part of receptors, and short leucine-rich sequences termed LxxLL motifs or nuclear receptor boxes present in coactivators. RXR-PPARgamma (retinoid X receptor-peroxisome proliferator-activated receptor-gamma) heterodimers play important roles in adipocyte and macrophage differentiation and have been implicated as therapeutic targets in diabetes, atherosclerosis, and cancer. Analysis of interactions between RXR-PPARgamma heterodimers and coactivator nuclear receptor boxes suggests that RXR and PPARgamma can distinguish among coactivators by recognizing distinct structural features of nuclear receptor boxes. The results also indicate that coactivator choice by RXR is mediated by three nonconserved amino acids of the nuclear receptor box. The ability of an optimized seven-amino acid nuclear receptor box to specifically interact with RXR and function as a selective inhibitor suggests the coactivator-binding pocket may serve as a new target for drug discovery.
激动剂与核受体的结合会导致受体结构发生构象变化，从而促进活化受体与共激活因子之间的相互作用。受体 - 共激活因子的相互作用是由受体部分上依赖激动剂形成的疏水口袋以及共激活因子中存在的称为LxxLL基序或核受体盒的富含亮氨酸的短序列介导的。视黄酸X受体 - 过氧化物酶体增殖物激活受体γ（RXR - PPARγ）异二聚体在脂肪细胞和巨噬细胞分化中起重要作用，并被认为是糖尿病、动脉粥样硬化和癌症的治疗靶点。对RXR - PPARγ异二聚体与共激活因子核受体盒之间相互作用的分析表明，RXR和PPARγ可以通过识别核受体盒的不同结构特征来区分共激活因子。结果还表明，RXR对共激活因子的选择是由核受体盒的三个非保守氨基酸介导的。优化的七氨基酸核受体盒与RXR特异性相互作用并作为选择性抑制剂发挥作用的能力表明，共激活因子结合口袋可能成为药物发现的新靶点。
