Small Molecule Modulation of the Archetypal UbiB protein COQ8
Murray, N. H.; Lewis, A.; Asquith, C. R. M.; Pabon, J. P. R.; Fang, Z.; Ptak, N.; Smith, R. W.; Vasta, J. D.; Zimprich, C. A.; Corona, C. R.; Robers, M. B.; Bingman, C. A.; Gross, M. L.; Henzler-Wildman, K.; Pagliarini, D. J.
Show 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 inhibitor and activator molecules 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. Second, using 1H-13C HMQC NMR and hydrogen-deuterium exchange mass spectrometry, we reveal that the CoQ precursor mimetic, 2-propylphenol (2-PP), modulates the quintessential UbiB KxGQ domain to increase COQ8A nucleotide affinity and ATPase activity. Our newfound chemical tools promise to lend new mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Molecular basis of the urate transporter URAT1 inhibition by gout drugs 98%
- Structure of a lasso peptide bound ETB receptor provides insights into the mechanism of GPCR inverse agonism 98%
- Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase 97%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.