通过膜固醇的平滑刺激驱动了子通路活动
Ishan Deshpande1, Jiahao Liang1, Danielle Hedeen2,3
1Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
Nature
|July 3, 2019
概括
的信号对于发育和再生至关重要. 研究人员阐明了SMO的结构,揭示了胆固醇
科学领域:
- 生物化学
- 分子生物学
- 结构生物学
背景情况:
- 对于胚胎发育和组织再生至关重要.
- 在基底细胞癌和脑髓母细胞瘤等癌症中.
- 精确的SMO激活机制仍然不清楚.
研究的目的:
- 确定活跃的小鼠平滑蛋白 (SMO) 的晶体结构.
- 阐明SMO通过其激动剂和胆固醇激活的结构基础.
- 了解SMO通过PTCH1的调节,并为治疗策略提供信息.
主要方法:
- 活动小鼠SMO与SAG21k和纳米体结合的X射线晶体.
- 进行分子动力学模拟.
- 信号通路的研究.
主要成果:
- 确定了活性SMO的晶体结构,揭示了其与激动剂SAG21k和稳定纳米体的相互作用.
- 对于SMO激活至关重要的胆固醇,与之前的模型相反,它与七个跨膜口袋结合.
- 提出了一个机制,在这种机制中,PTCH1的失活使得醇能够进入SMO,从而驱动激活.
结论:
- 这项研究揭示了SMO激活的结构机制,其中包括胆固醇在跨膜口袋中的结合.
- 这为黑信号中的PTCH1-SMO调节提供了结构基础.
- 这些发现为开发克服SMO抑制剂耐药性的策略提供了洞察力.
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