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Small-molecule inhibition of the archetypal UbiB protein COQ8.

ABSTRACT: 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.

SUBMITTER: Murray NH

PROVIDER: S-EPMC9898131 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Small-molecule inhibition of the archetypal UbiB protein COQ8.

Murray Nathan H NH Asquith Christopher R M CRM Fang Zixiang Z East Michael P MP Ptak Naomi N Smith Robert W RW Vasta James D JD Zimprich Chad A CA Corona Cesear R CR Robers Matthew B MB Johnson Gary L GL Bingman Craig A CA Pagliarini David J DJ

Nature chemical biology 20221027 2

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 repurpose ...[more]

PMID: 36302899

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