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Small-molecule inhibition of the archetypal UbiB protein COQ8.
Murray, Nathan H; Asquith, Christopher R M; Fang, Zixiang; East, Michael P; Ptak, Naomi; Smith, Robert W; Vasta, James D; Zimprich, Chad A; Corona, Cesear R; Robers, Matthew B; Johnson, Gary L; Bingman, Craig A; Pagliarini, David J.
Affiliation
  • Murray NH; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
  • Asquith CRM; Morgridge Institute for Research, Madison, WI, USA.
  • Fang Z; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
  • East MP; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Ptak N; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Smith RW; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
  • Vasta JD; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
  • Zimprich CA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Corona CR; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
  • Robers MB; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
  • Johnson GL; Promega Corporation, Madison, WI, USA.
  • Bingman CA; Promega Corporation, Madison, WI, USA.
  • Pagliarini DJ; Promega Corporation, Madison, WI, USA.
Nat Chem Biol ; 19(2): 230-238, 2023 02.
Article in En | MEDLINE | ID: mdl-36302899
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Saccharomyces cerevisiae / Saccharomyces cerevisiae Proteins Limits: Humans Language: En Journal: Nat Chem Biol Journal subject: BIOLOGIA / QUIMICA Year: 2023 Document type: Article Affiliation country:
Fulltext
Add to My VHL
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Saccharomyces cerevisiae / Saccharomyces cerevisiae Proteins Limits: Humans Language: En Journal: Nat Chem Biol Journal subject: BIOLOGIA / QUIMICA Year: 2023 Document type: Article Affiliation country: