在ARNT PAS-B域内和内的小分子配体结合点的识别
bioRxiv : the preprint server for biology
|November 14, 2023
概括
研究人员探索了用小分子准ARNT PAS-B域来调节信号通路. 他们确定了抑制剂的特定结合部位,指导开发更强大的联合激活器调节器.
科学领域:
- 分子生物学分子生物学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 由于其结构,转录因子很难以小分子为目标.
- 自然联体调节的转录因子提供了例外,比如HIF-2.
- 针对ARNT PAS-B域可以调节多个ARNT介导的途径.
研究的目的:
- 为了研究ARNT PAS-B域的小分子向.
- 为了识别ARNT PAS-B上的联结位点和热点.
- 为指导新型ARNT协激活剂抑制剂的开发提供指导.
主要方法:
- 一个片段库的溶液核磁共振选.
- 分子动力学 (MD) 模拟.
- 组合对接以识别联结热点.
主要成果:
- 两种抑制剂 (KG-548,KG-655) 结合了参与HIF-2二分化和协同激活剂招募的β片表面.
- KG-548只结合β片表面;KG-655结合表面和内部腔.
- 第三个连接体 (KG-279) 优先结合内部腔,促进ARNT PAS-B的同质化.
结论:
- 实现了ARNT PAS-B带结合部位的详细映射.
- 这些发现为设计更强大的ARNT联合激活剂抑制剂提供了基础.
- 这种方法可能使ARNT介导信号的同时调制成为可能.
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