The molecular basis of human FN3K mediated phosphorylation of glycated substrates Journal Article
| Authors: | Garg, A.; On, K. F.; Xiao, Y.; Elkayam, E.; Cifani, P.; David, Y.; Joshua-Tor, L. |
| Article Title: | The molecular basis of human FN3K mediated phosphorylation of glycated substrates |
| Abstract: | Glycation, a non-enzymatic post-translational modification occurring on proteins, can be actively reversed via site-specific phosphorylation of the fructose-lysine moiety by FN3K kinase, to impact the cellular function of the target protein. A regulatory axis between FN3K and glycated protein targets has been associated with conditions like diabetes and cancer. However, the molecular basis of this relationship has not been explored so far. Here, we determined a series of crystal structures of HsFN3K in the apo-state, and in complex with different nucleotide analogs together with a sugar substrate mimic to reveal the features important for its kinase activity and substrate recognition. Additionally, the dynamics in sugar substrate binding during the kinase catalytic cycle provide important mechanistic insights into HsFN3K function. Our structural work provides the molecular basis for rational small molecule design targeting FN3K. © The Author(s) 2025. |
| Keywords: | controlled study; protein expression; protein phosphorylation; unclassified drug; genetics; mass spectrometry; metabolism; protein degradation; protein; protein binding; in vitro study; structure activity relation; phosphorylation; molecular cloning; chemistry; protein processing; protein processing, post-translational; cell culture; protein purification; phosphotransferases (alcohol group acceptor); substrate specificity; glycosylation; crystal structure; models, molecular; crystallography, x-ray; crystallization; x ray crystallography; enzyme specificity; phosphotransferase; diabetes; molecular model; polyacrylamide gel electrophoresis; x ray diffraction; substrate; affinity chromatography; peptides and proteins; liquid chromatography-mass spectrometry; size exclusion chromatography; kinase assay; crystal; baculovirus expression system; cation exchange; cancer; humans; human; article; ultra performance liquid chromatography; column chromatography; glycation; sf9 cell line; glycated protein; protein fructosamine 3 kinase; fructosamine-3-kinase |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-22 |
| Start Page: | 941 |
| Language: | English |
| DOI: | 10.1038/s41467-025-56207-z |
| PUBMED: | 39843453 |
| PROVIDER: | scopus |
| PMCID: | PMC11754801 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
