人类二甲基糖醇O-乙转移酶1的结构和机制
Lie Wang1, Hongwu Qian2, Yin Nian1,3
1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
Nature
|May 21, 2020
概括
在脂肪吸收和储存方面,二甲基糖醇O- 乙酸转移酶1 (DGAT1) 是至关重要的. 研究人员揭示了它的结构,
科学领域:
- 生物化学
- 结构生物学
- 分子生物学
背景情况:
- 甲基糖醇O-转移酶1 (DGAT1) 合成三甲基糖化物,这对饮食中的脂肪吸收和储存至关重要.
- DGAT1 是膜结合的O- 乙转移酶 (MBOAT) 超级家族的一部分,参与脂质和蛋白质的乙化.
- 了解DGAT1的机制和结构对于治疗向至关重要,但目前是有限的.
研究的目的:
- 确定人类DGAT1的三维结构.
- 阐明DGAT1的基质识别和催化机制.
- 为合理设计DGAT1抑制剂提供结构基础.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来获得人类DGAT1的结构.
- 它的结构是用一个-CoA基质复合确定的.
- 四元结构 (二元和四元) 和N端相互作用的分析.
主要成果:
- 人类DGAT1的冷EM结构显示出一个独特的MBOAT折叠,包括九个跨膜螺旋.
- 膜内保留的空洞腔封闭了催化残留物,并具有明显的基板进入点.
- DGAT1作为具有相似活性的同位体或同位四聚体,需要N端相互作用来发挥作用.
结论:
- 确定结构为DGAT1嵌入膜的催化机制提供了前所未有的洞察力.
- 显著的基质通道表明了基质结合和化的一种特定模式.
- 这些结构信息对于开发代谢疾病的向疗法至关重要.
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