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通过异oprenoid二酸盐抑制FicD介导的AMPylation和deAMPylation通过异oprenoid二酸盐

Aubrie M Blevins^1,2, Wei Peng^1,3, Lisa N Kinch^1,3

¹Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Proceedings of the National Academy of Sciences of the United States of America

|March 4, 2026

概括

研究人员发现,法纳西尔-酸盐抑制了FicD,这是未折叠蛋白质反应 (UPR) 的关键调节器. 这一发现为与UPR相关的遗传性疾病提供了潜在的治疗策略,通过区分引起疾病的FicD变体.

科学领域:

生物化学生物化学
分子生物学分子生物学
细胞生物学细胞生物学

背景情况:

展开的蛋白质反应 (UPR) 对于细胞平衡至关重要,由像BiP这样的陪伴者调节.
在不同压力条件下,FicD通过AMPylation/deAMPylation调节BiP活动,影响UPR.
包括FicD在内的UPR机制中的遗传变异与遗传性疾病有关,这突显了了解FicD监管的必要性.

研究的目的:

通过使用高通量选平台,识别调节FicD活动的小分子代谢物.
为了阐明FicD抑制的机制被识别的代谢物.
为了区分抑制剂对与疾病相关的FicD变体的影响.

主要方法:

使用的质谱学集成与平衡透析以发现系统地 (MIDAS) 透,以进行公正的查.
进行了FicD-抑制剂复合物的生化表征和晶体结构分析.
测试了法纳西尔-酸盐对与遗传性疾病相关的特定FicD变体的抑制作用.

主要成果:

在MIDAS中,Geranyl-Pyrophosphate和Farnesyl-Pyrophosphate被确定为FicD调节剂.
这两种化合物都强烈抑制了FicD介导的AMPylation和deAMPylation.
晶体结构揭示了法纳西尔-酸盐通过模仿ATP结合来竞争性抑制FicD.
法内西尔-酸盐可以选择性地抑制与遗传性性相关的FicD变体,但不能抑制新生儿糖尿病.

结论:

法尔内西尔-酸盐和日拉尼尔-酸盐是新型FicD抑制剂.
这项研究为FicD通过美酸途径中间体的抑制提供了结构基础.
这项研究区分了引起疾病的FicD变体,为针对性药理干预在UPR相关疾病提供了洞察力.

关键词:

在AMPylation中进行AMPylation.科幻小说科幻小说在PTM的PTM.异烯酸二酸盐是什么不折叠的蛋白质反应反应

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