Small-molecule inhibition of the archetypal UbiB protein COQ8

Nathan H Murray; Christopher R M Asquith; Zixiang Fang; Michael P East; Naomi Ptak; Robert W Smith; James D Vasta; Chad A Zimprich; Cesear R Corona; Matthew B Robers; Gary L Johnson; Craig A Bingman; David J Pagliarini

doi:10.1038/s41589-022-01168-3

Small-molecule inhibition of the archetypal UbiB protein COQ8

Nat Chem Biol. 2023 Feb;19(2):230-238. doi: 10.1038/s41589-022-01168-3. Epub 2022 Oct 27.

Authors

Nathan H Murray^{1

2

3}, Christopher R M Asquith^{4

5

6}, Zixiang Fang³, Michael P East⁴, Naomi Ptak¹, Robert W Smith¹, James D Vasta⁷, Chad A Zimprich⁷, Cesear R Corona⁷, Matthew B Robers⁷, Gary L Johnson⁴, Craig A Bingman¹, David J Pagliarini^{8

9

10

11

12}

Affiliations

¹ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
² Morgridge Institute for Research, Madison, WI, USA.
³ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ 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.
⁶ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
⁷ Promega Corporation, Madison, WI, USA.
⁸ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA. pagliarini@wustl.edu.
⁹ Morgridge Institute for Research, Madison, WI, USA. pagliarini@wustl.edu.
¹⁰ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA. pagliarini@wustl.edu.
¹¹ Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA. pagliarini@wustl.edu.
¹² Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. pagliarini@wustl.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Humans
Saccharomyces cerevisiae Proteins* / metabolism
Saccharomyces cerevisiae* / metabolism
Ubiquinone / chemistry
Ubiquinone / pharmacology

Substances

ubiquinone 8
Ubiquinone
Saccharomyces cerevisiae Proteins
COQ8 protein, S cerevisiae

Abstract

Publication types

MeSH terms

Substances

Grants and funding