小分子抑制典型的 UbiB 蛋白 COQ8。
Small-molecule inhibition of the archetypal UbiB protein COQ8.
机构信息
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
Morgridge Institute for Research, Madison, WI, USA.
出版信息
Nat Chem Biol. 2023 Feb;19(2):230-238. doi: 10.1038/s41589-022-01168-3. Epub 2022 Oct 27.
Small-molecule tools have enabled mechanistic investigations and therapeutic targeting of the protein kinase-like (PKL) superfamily. However, such tools are still lacking for many PKL members, including the highly conserved and disease-related UbiB family. Here, we sought to develop and characterize an inhibitor for the archetypal UbiB member COQ8, whose function is essential for coenzyme Q (CoQ) biosynthesis. Guided by crystallography, activity assays and cellular CoQ measurements, we repurposed the 4-anilinoquinoline scaffold to selectively inhibit human COQ8A in cells. Our chemical tool promises to lend mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction.
小分子工具已被用于蛋白激酶样（PKL）超家族的机制研究和治疗靶向。然而，对于许多 PKL 成员，包括高度保守和与疾病相关的 UbiB 家族，仍然缺乏这样的工具。在这里，我们试图开发和表征一种针对典型的 UbiB 成员 COQ8 的抑制剂，其功能对于辅酶 Q（CoQ）生物合成至关重要。受晶体学、活性测定和细胞 CoQ 测量的指导，我们重新利用了 4-苯胺基喹啉支架来选择性地抑制细胞中的人 COQ8A。我们的化学工具有望为这些广泛存在但研究不足的蛋白质的活性提供机制上的见解，并为与它们功能障碍相关的人类疾病提供潜在的治疗策略。
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