一组化学相关的孕激素受体调节剂激动剂和拮抗剂的作用机制研究
Structural basis for agonism and antagonism for a set of chemically related progesterone receptor modulators.
机构信息
Department of Molecular Design and Informatics, DMPK, MSD, PO Box 20, 5340 BH Oss, The Netherlands.
出版信息
J Biol Chem. 2011 Oct 7;286(40):35079-86. doi: 10.1074/jbc.M111.273029. Epub 2011 Aug 17.
Abstract
The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes.
摘要
孕激素受体能够与大量不同的配体结合，引发从完全激动作用到完全拮抗作用以及两者之间多种混合模式的广泛转录反应。我们在这里描述了两个与结构相关但功能不同的系列化合物结合的新孕激素受体配体结合域 X 射线结构，它们显示出与其激动剂或拮抗剂性质相对应的不同结合模式。此外，我们还展示了第三个孕激素受体配体结合域二聚体，其中单体 A 结合激动剂，单体 B 结合拮抗剂，其结合模式与之前的观察结果一致，即该系列的激动剂和拮抗剂采用不同的结合模式。
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