通过计算和生物物理方法识别和抑制PIN1-NRF2蛋白-蛋白相互作用
Adem Ozleyen1,2,3, Gizem Nur Duran4, Serhat Donmez5,6
1Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, LE1 7RH, UK.
Scientific reports
|March 15, 2025
概括
研究人员研究了与核因子红色素2相关的因子2 (NRF2) 和Pin1基烯基 cis-trans异构酶 (PIN1) 之间的相互作用. 该研究确定了关键的结合部位和评估的抑制剂,其中KPT-6566显示了NRF2-PIN1相互作用的强烈抑制.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 核因子红色素2相关因子2 (NRF2) 是一种调节细胞保护基因的转录因子.
- NRF2与Pin1基基转异构酶 (PIN1) 之间的相互作用对于调节NRF2的细胞保护作用至关重要,但仍然不太了解.
研究的目的:
- 通过计算,生物物理和生物化学方法阐明PIN1和NRF2之间的结合相互作用.
- 为了确定涉及PIN1-NRF2相互作用的关键残留物.
- 评估已知PIN1抑制剂对NRF2-PIN1相互作用的抑制潜力.
主要方法:
- 计算建模用于预测绑定站点.
- 生物物理光极化 (FP) 试验测量结合亲和力.
- 使用质谱测量分析抑制机制的生物化学测试.
- 合成和测试NRF2模仿.
主要成果:
- 计算分析确定了PIN1的WW域中的特定残留物,这些残留物对于NRF2结合至关重要.
- FP试验证实了这些发现,并显示Pintide显著降低了NRF2的结合亲和力.
- KPT-6566证明了PIN1-NRF2相互作用的最强大的抑制 (IC50:0.3-1.4μM).
- 质谱学揭示了KPT-6566通过联添加对PIN1进行共价性修改.
结论:
- 这项研究为PIN1-NRF2相互作用机制提供了详细的见解.
- 通过生物物理实验确定了关键残留物和验证了计算预测.
- KPT-6566是一种强大的NRF2-PIN1相互作用抑制剂,是进一步研究的宝贵工具.
- 这些发现可能有助于在癌症治疗中开发针对NRF2细胞保护功能的药物.
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