类固醇激素部分激动剂活性理论。

IF 0.7 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Carson C Chow, Karen M Ong, Benjamin Kagan, S Stoney Simons
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引用次数: 6

摘要

在各种条件下,抗类固醇药物的残余部分激动剂活性(PAA)的不同量长期以来在临床应用中是有用的,但在很大程度上仍未得到解释。一种特定的拮抗剂不仅对同一细胞内的多个基因具有不平等的诱导作用,而且具有同一基因的同一抗类固醇的活性也会随着众多辅助因子浓度的变化而变化。使用糖皮质激素受体作为模型系统,我们最近成功地从第一性原理构建了一个理论,该理论准确地描述了辅助因子如何调节激动剂类固醇调节基因诱导和基因抑制的能力。我们现在将这个框架扩展到抗类固醇在基因诱导中的作用。该理论解释了为什么PAA的变化不能简单地用配体对受体亲和力的差异来解释,而需要在整个反应序列的第二步或位点上起作用。该理论还提供了一种定位第二位点位置的方法,相对于浓度限制步骤(CLS), CLS是先前确定的糖皮质激素调节的转激活步骤,在基因诱导的整个事件序列中总是发生在相同的位置。最后,该理论预测,拮抗剂配体的类别可能根据其最大PAA和多余的辅助因子进行分组,并且在整个基因诱导过程的同一步骤中,每一类成员的不同之处在于它们的作用方式。因此,该理论现在可以预测不同的辅助因子如何调节抗类固醇PAA,这对于开发更具选择性的拮抗剂应该是非常宝贵的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Theory of partial agonist activity of steroid hormones.

Theory of partial agonist activity of steroid hormones.

Theory of partial agonist activity of steroid hormones.

Theory of partial agonist activity of steroid hormones.

The different amounts of residual partial agonist activity (PAA) of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS), which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

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来源期刊
AIMS Molecular Science
AIMS Molecular Science BIOCHEMISTRY & MOLECULAR BIOLOGY-
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审稿时长
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