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 prote...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56207-z |
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| author | Ankur Garg Kin Fan On Yang Xiao Elad Elkayam Paolo Cifani Yael David Leemor Joshua-Tor |
| author_facet | Ankur Garg Kin Fan On Yang Xiao Elad Elkayam Paolo Cifani Yael David Leemor Joshua-Tor |
| author_sort | Ankur Garg |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-532844cf28094904946ab01858dd1eda |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-532844cf28094904946ab01858dd1eda2025-01-26T12:41:32ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-025-56207-zThe molecular basis of Human FN3K mediated phosphorylation of glycated substratesAnkur Garg0Kin Fan On1Yang Xiao2Elad Elkayam3Paolo Cifani4Yael David5Leemor Joshua-Tor6Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring HarborCold Spring Harbor Laboratory, One Bungtown Road, Cold Spring HarborChemical Biology Program, Memorial Sloan Kettering Cancer CenterCold Spring Harbor Laboratory, One Bungtown Road, Cold Spring HarborCold Spring Harbor Laboratory, One Bungtown Road, Cold Spring HarborChemical Biology Program, Memorial Sloan Kettering Cancer CenterCold Spring Harbor Laboratory, One Bungtown Road, Cold Spring HarborAbstract 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.https://doi.org/10.1038/s41467-025-56207-z |
| spellingShingle | Ankur Garg Kin Fan On Yang Xiao Elad Elkayam Paolo Cifani Yael David Leemor Joshua-Tor The molecular basis of Human FN3K mediated phosphorylation of glycated substrates Nature Communications |
| title | The molecular basis of Human FN3K mediated phosphorylation of glycated substrates |
| title_full | The molecular basis of Human FN3K mediated phosphorylation of glycated substrates |
| title_fullStr | The molecular basis of Human FN3K mediated phosphorylation of glycated substrates |
| title_full_unstemmed | The molecular basis of Human FN3K mediated phosphorylation of glycated substrates |
| title_short | The molecular basis of Human FN3K mediated phosphorylation of glycated substrates |
| title_sort | molecular basis of human fn3k mediated phosphorylation of glycated substrates |
| url | https://doi.org/10.1038/s41467-025-56207-z |
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