甲状腺素通过单碳酸盐载体运输的分子机制
Matteo Tassinari1, Giorgia Tanzi1, Francesco Maggiore1
1Human Technopole, Milano, Italy.
Nature communications
|May 14, 2025
概括
对甲状腺激素载体单碳酸盐载体8 (MCT8) 和MCT10的结构洞察力揭示了激素运输和疾病的机制. 这项研究阐明了这些载体的功能以及MCT8缺乏的分子基础.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 分子医学是分子医学.
背景情况:
- 甲状腺激素 (甲状腺素和三甲状腺素) 调节关键的发育和代谢功能.
- 血载体,特别是单碳酸盐载体8 (MCT8) 和MCT10,促进甲状腺激素的运输.
- 缺乏MCT8会导致严重的神经发育和代谢障碍,强调了解其传输机制的重要性.
研究的目的:
- 通过MCT8和MCT10.0阐明甲状腺激素运输的分子机制.
- 在不同功能状态下确定人类MCT8和MCT10的结构.
- 调查MCT8缺乏和抑制作用的结构基础.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定高分辨率结构.
- 获得了无带和甲状腺素结合的MCT8 (面向外) 和甲状腺素结合的MCT10 (面向内) 的结构.
- 还确定了患者衍生的MCT8突变体和MCT8与抑制剂西利克里斯结合的结构.
主要成果:
- 结构分析显示,在甲状腺素结合时,保留门残留物和形状变化,促进结合体释放.
- 一个来自患者的MCT8突变结构显示出微妙的形状变化,解释了减少的运输活动.
- 结合锡利克里斯的MCT8的结构阐明了抑制剂的机制和特异性.
结论:
- 这项研究为MCT8和MCT10的甲状腺激素运输机制提供了前所未有的结构洞察力.
- 这些发现有助于我们更好地了解甲状腺激素的正常和失调运输,这对MCT8缺乏有影响.
- 这些结构数据为开发针对甲状腺激素运输的治疗策略提供了基础.
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