人类propionyl-CoA碳氧酶的纳米尺度构造动力学
Huifang Yan1, Fengyun Ni2, Qinghua Wang3
1Multiscale Research Institute of Complex Systems, Fudan University, Shanghai 200433, China; School of Life Sciences, Fudan University, Shanghai 200433, China.
Structure (London, England : 1993)
|November 6, 2025
概括
解决了propionyl-CoA碳酸酶 (PCC) 的结构,揭示了生物碳酸载体蛋白的运动如何同步催化. 这为酸血症和潜在的代谢疗法提供了洞察力.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 代谢障碍 代谢障碍 代谢障碍
背景情况:
- propionyl-CoA 核糖酶 (PCC) 是一个关键的线粒体酶,用于 propionyl-CoA 代谢.
- 人类PCC (hPCC) 的缺陷导致 propionic acidemia,一种严重的代谢障碍.
- 对于hPCC的催化功能和疾病机制的结构基础尚未完全理解.
研究的目的:
- 在各种功能状态下阐明人类PCC (hPCC) 的高分辨率结构.
- 了解生物碳素载体蛋白 (BCCP) 转位的机制及其在催化中的作用.
- 研究疾病相关突变如何影响hPCC结构和功能.
主要方法:
- 使用高分辨率冷电子显微镜 (cryo-EM) 来确定hPCC的结构.
- 捕获了四种不同的状态:未结合,ADP结合,AMPPNP结合和ATP/基质结合.
- 对10种与疾病相关的变体进行了结构和生化分析.
主要成果:
- 低温电磁结构揭示了BCCP域在活性位点之间转移期间的完整轨迹.
- 核酸入的B-子子域被证明对同步催化与BCCP运动至关重要.
- 发现疾病相关变异的突变会破坏关键域界面和基本动态运动.
结论:
- 该研究通过详细的结构见解定义了通过详细的结构见解来管理hPCC功能的机制原理.
- 建立了一个结构框架,以了解酸血症和相关疾病.
- 这些发现为开发新的治疗策略奠定了基础,包括工程酶替代物或调节器.
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