一个膜结合的O-转移酶的晶体结构
Dan Ma1, Zhizhi Wang1, Christopher N Merrikh2
1Department of Biological Structure, University of Washington, Seattle, WA, USA.
Nature
|October 5, 2018
概括
晶体结构揭示了DltB的分子结构,DltB是一种与膜结合的O-转移酶 (MBOAT),参与细菌细胞壁的修饰. 这些发现阐明了MBOAT机制,并为开发新的治疗抑制剂提供了基础.
科学领域:
- 生物化学
- 结构生物学
- 微生物学
背景情况:
- 膜结合的O-转移酶 (MBOAT) 是所有生命形式的关键组成的跨膜酶.
- 在脂质生物合成,脂重塑和分泌蛋白质的脂质修饰中,MBOATs起着至关重要的作用.
- 尽管它们作为药物点的重要性,但MBOAT的分子架构和机制在很大程度上仍未被描述.
研究的目的:
- 确定单独和与其D-alanyl捐赠蛋白DltC复合的DltB,一种细菌MBOAT的晶体结构.
- 阐明DLTB的分子结构和功能机制,特别是其在细胞壁中D-alanylation中的作用.
- 提供不同生物体中MBOATs保存的结构核心和催化机制的见解.
主要方法:
- 采用X射线结晶学来获得DltB及其与DltC复合的高分辨率结构.
- 用定位突变来研究关键残留物的功能,包括催化和DltC结合部位.
- 在细菌DltB和脊椎动物MBOAT之间进行了结构导向的序列比较.
主要成果:
- 晶体结构显示DltB具有11个跨膜螺旋环, 屏蔽一个导致狭窄的细胞内道的细胞外道.
- 一个保存的催化希斯蒂丁残留物位于道的底部,通过道连接到DltC.
- 催化或DltC结合部位的突变取消了D-alanylation并使Bacillus subtilis对细胞壁应激敏感,表明跨膜催化.
结论:
- 确定结构为MBOAT的分子结构和机制提供了前所未有的洞察力.
- 这些发现表明各种生物体的MBOAT中保留了结构核心和类似的催化机制.
- 这些结构作为理解MBOAT结构功能关系和合理设计MBOAT抑制剂的模板.
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