Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor
Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor
复制标题
DOI：
10.1038/nature02112
复制
发表时间：
2003-11-06
期刊：
影响因子：
64.8
通讯作者：
Moras, D
中科院分区：
文献类型：
--
作者：
Billas, IML;Iwema, T;Moras, D
蜕皮甾类激素通过与蜕皮激素受体（EcR）（一种配体诱导的核转录因子）结合，协调昆虫发育的主要阶段，特别是蜕皮和变态（1，2）。为了结合配体或DNA，EcR必须与类维生素A-X受体的同源物超气门（USP）形成异源二聚体（3-5）。在这里，我们报告的晶体结构的蛾Heliothis virescens EcR-USP异二聚体的配体结合结构域的复杂的蜕皮甾体ponasterone A和非甾体，鳞翅目特异性激动剂BYI 06830用于农业化学害虫防治。EcR-USP的两种结构强调了异源二聚化作为脊椎动物和无脊椎动物共同的一般机制的普遍性。与甾体和非甾体配体的复合物中的EcR结构的比较揭示了根本不同的且仅部分重叠的配体结合口袋，其不能通过分子建模和对接研究预测（6，7）。这些发现为设计针对昆虫的环境安全杀虫剂提供了新的视角。EcR中的配体依赖性结合口袋的概念提供了对核受体对其配体的模制的深入了解，并且对人类核受体具有潜在的应用。
The ecdysteroid hormones coordinate the major stages of insect development, notably moulting and metamorphosis, by binding to the ecdysone receptor (EcR); a ligand-inducible nuclear transcription factor(1,2). To bind either ligand or DNA, EcR must form a heterodimer with ultraspiracle (USP), the homologue of retinoid-X receptor(3-5). Here we report the crystal structures of the ligand-binding domains of the moth Heliothis virescens EcR - USP heterodimer in complex with the ecdysteroid ponasterone A and with a non-steroidal, lepidopteran-specific agonist BYI06830 used in agrochemical pest control. The two structures of EcR - USP emphasize the universality of heterodimerization as a general mechanism common to both vertebrates and invertebrates. Comparison of the EcR structures in complex with steroidal and non-steroidal ligands reveals radically different and only partially overlapping ligand-binding pockets that could not be predicted by molecular modelling and docking studies(6,7). These findings offer new perspectives for the design of insect-specific, environmentally safe insecticides. The concept of a ligand-dependent binding pocket in EcR provides an insight into the moulding of nuclear receptors to their ligand, and has potential applications for human nuclear receptors.