人类酸盐载体NaCT的结构和抑制机制
David B Sauer1,2, Jinmei Song1,2, Bing Wang3
1Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA.
Nature
|February 18, 2021
概括
研究人员确定了依赖的酸转运体 (NaCT) 的结构,以了解抑制剂如何阻断脂肪酸合成. 这揭示了潜在的抗肥胖药物的机制以及对SLC13A5的洞察力.
科学领域:
- 生物化学
- 结构生物学
- 分子运输
背景情况:
- 酸盐是一种重要的代谢中间体,也是脂肪酸合成的调节剂.
- 肝细胞的酸盐吸收由依赖的酸盐运输体 (NaCT) 介导,这是潜在的抗肥胖药物标.
- 编码NaCT的SLC13A5突变会导致新生儿.
研究的目的:
- 通过小分子抑制剂阐明NACT抑制的结构基础.
- 了解 NaCT 调节酸盐运输的机制.
- 为开发选择性NaCT抑制剂和理解SLC13A5提供结构框架.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定人类NaCT的结构.
- 获得了NaCT与酸盐和小分子抑制剂复合的结构.
- 进行了对同类载体的NaCT结构的比较分析.
主要成果:
- 低温-EM结构显示了抑制剂如何与酸盐结合到相同的部位,从而阻止NaCT运输循环.
- 它的NaCT抑制剂结构解释了它对相关的二碳酸盐载体的选择性.
- 这些结构提供了关于NaCT突变如何导致的见解.
结论:
- 确定的NaCT结构提供了对酸盐运输抑制的分子理解.
- 这些发现有助于设计针对抗肥胖症的改进和选择性NaCT抑制剂.
- 这些结构数据有助于了解SLC13A5的分子基础.
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