将类固醇激素放置在人类的ABCC3转运器中,揭示了一个兼容的两基质结合口袋
Jie Wang1,2, Xu Li1,2, Fang-Fang Wang1,2
1Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
The EMBO journal
|July 24, 2023
概括
研究人员使用冷EM可视化了ABCC3转运器,揭示了它与结合激素结合时的结构. 这为ABCC3如何与基质结合提供了洞察力,有助于药物设计.
科学领域:
- 生物化学 生化学
- 结构生物学 结构生物学
- 分子生物学分子生物学
背景情况:
- 人类ABCC3转运体 (MRP3) 对于消除内源代谢产物和药物至关重要.
- ABCC3的功能障碍与诸如妊娠的肝脏内胆固醇症等疾病有关.
- 了解ABCC3的基质结合是解决相关病理的关键.
研究的目的:
- 为了确定人类ABCC3.3.的高分辨率结构.
- 阐明结合性激素与ABCC3.3.的结合机制.
- 为设计ABCC3向抑制剂提供结构基础.
主要方法:
- 低温电子显微镜 (cryo-EM) 以获得高分辨率的结构.
- 复杂的形成与特定的结合激素:β-雌激醇17-(β-D-葡萄化物) 和脱二二硫酸盐.
- 针对位点的突变发生和ATPase活性测试以功能化结构发现.
主要成果:
- 确定了ABCC3的三个冷EM结构:阿波形式和两个与激素结合的复合体.
- 结构分析揭示了一个两基质结合口袋,不对称地容纳结合激素.
- 类固醇核以中心方式结合,而结合组则由不同的水友性区域稳定.
结论:
- 在ABCC3中,它拥有一个多功能基质结合口袋,能够结合多种合激素.
- 这些结构洞察力解释了ABCC3对这些基板的运输机制.
- 这些发现为开发针对ABCC3.3的新型治疗策略和抑制剂提供了基础.
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