猪介导的Wnt化机制和抑制
Yang Liu1, Xiaofeng Qi1, Linda Donnelly1
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|July 13, 2022
概括
这项研究揭示了猪 (PORCN) 修改Wnt蛋白的机制,这对Wnt信号提供至关重要. 结构显示抗癌药物LGK974如何通过阻断基质接入来抑制PORCN,从而促进癌症治疗的发展.
科学领域:
- 生物化学
- 结构生物学
- 分子生物学
背景情况:
- Wnt信号对于胚胎发育和组织平衡至关重要.
- 异常的Wnt信号与各种癌症有关.
- Wnt 信号需要由 Porcupine (PORCN) 进行棕豆化.
研究的目的:
- 通过PORCN阐明Wnt蛋白的结构机制.
- 了解抗癌药物LGK974对PORCN的抑制机制.
- 为开发用于癌症治疗的新型PORCN抑制剂提供见解.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定人类PORCN的四个高分辨率结构.
- 获得了与棕醇-CoA,LGK974,WNT3A发针2 (WNT3Ap) 和WNT3Ap模拟物复合的PORCN结构.
主要成果:
- 结构显示WNT3A从光线侧插入PORCN,而棕醇-CoA从细胞质侧进入.
- 催化希斯蒂丁促进了棕醇基向Wnt发针2的转移.
- LGK974通过与棕醇-CoA位点结合来抑制PORCN,从而阻止基质的进入.
结论:
- 这项工作为PORCN的Wnt化提供了详细的机制理解.
- 这些发现推动了PORCN抑制剂作为异常Wnt信号驱动的癌症治疗策略的发展.
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