胆酸输送器中交替接入机制的结构基础
Xiaoming Zhou1, Elena J Levin2, Yaping Pan3
11] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [3].
Nature
|December 10, 2013
概括
胆酸载体如ASBT对于胆固醇代谢至关重要,是潜在的药物标. 新的结构揭示了这些载体是如何将胆酸和通过膜移动的,这有助于药物开发.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 膜运输 运输 膜运输
背景情况:
- 从胆固醇中合成的胆汁酸对于脂质吸收至关重要,并经历肠肝循环.
- 纳+依赖性胆酸载体NTCP和ASBT在人体中促进胆酸的再吸收.
- 由于其在胆酸再吸收中的作用,ASBT是高胆固醇血症的关键药物标.
研究的目的:
- 通过ASBT阐明胆酸和运输的分子机制.
- 了解基质选择性和运输动态的结构基础.
- 为合理设计针对ASBT的药物提供见解.
主要方法:
- 在脂质环境中确定了Yersinia frederiksenii ASBT同类物 (ASBTYf) 的两个晶体结构.
- 分析了与和胆酸的合运输相关的结构变化.
- 比较结构以推断运输机制和路径.
主要成果:
- 揭示了ASBTYf.中基质结合域的大型刚体旋转.
- 从膜的两侧证明了保存的"交叉"区域的交替可访问性.
- 提供了胆酸和Na ((+) 跨膜转移的结构基础.
结论:
- 观察到的域旋转机制解释了ASBT如何促进合运输.
- 结构性见解有助于理解胆酸和Na+运动.
- 这些发现推动了基于ASBT的治疗方法的开发,用于治疗与胆固醇有关的疾病.
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