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Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists.
Medicinal Research Reviews ( IF 13.3 ) Pub Date : 2001-10-19 , DOI: 10.1002/med.1024
U Egner 1 , N Heinrich , M Ruff , M Gangloff , A Mueller-Fahrnow , J M Wurtz
Affiliation  

The aim of this study is to compare crystal structures of nuclear receptor ligand binding domains in complex with different agonists and partial agonists to achieve a better understanding of the three-dimensional structures and their ligand-induced conformational changes. This led to the identification of structurally conserved "rigid" regions and more flexible parts of the proteins. The analysis was found to be of great value in fitting selected non-steroidal compounds into the human estrogen receptor alpha (hER alpha) ligand binding pocket. The experimentally determined binding affinities for a number of 2-aryl indoles and 2-aryl indenones are in good agreement with the subsequently modeled binding interactions. To date, no crystal structure is published for a complex with a pure antagonist. We therefore used the available structural information on complexes with partial agonists and the crystal structure of a mutant protein in complex with estradiol displaying a similar conformation to predict binding interactions for antagonists. The results are discussed in detail.

中文翻译:

不同的配体-不同的受体构象:hER alpha LBD与激动剂和拮抗剂复合的模型。

这项研究的目的是比较具有不同激动剂和部分激动剂的核受体配体结合域的晶体结构,以更好地理解三维结构及其配体诱导的构象变化。这导致鉴定了结构保守的“刚性”区域和蛋白质的更柔性部分。发现该分析对于将选定的非甾体化合物装配到人雌激素受体α(hERα)配体结合袋中具有重要价值。实验确定的许多2-芳基吲哚和2-芳基茚满的结合亲和力与随后建模的结合相互作用非常吻合。迄今为止,尚未公开具有纯拮抗剂的复合物的晶体结构。因此,我们使用了具有部分激动剂的复合物的可用结构信息以及与雌二醇复合的突变蛋白的晶体结构,显示出相似的构象,以预测拮抗剂的结合相互作用。详细讨论了结果。
更新日期:2019-11-01
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