小分子
超家族
计算生物学
功能(生物学)
药物发现
生物
生物化学
细胞生物学
化学
基因
作者
Nathan H. Murray,Christopher R. M. Asquith,Zixiang Fang,Michael P. East,Naomi Ptak,Robert W. Smith,James D. Vasta,Chad Zimprich,Cesear Corona,Matthew B. Robers,Gary L. Johnson,C.A. Bingman,David J. Pagliarini
标识
DOI:10.1038/s41589-022-01168-3
摘要
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.
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