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| Item Type: | Article |
|---|---|
| Title: | An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor |
| Creators: |
Aguirre, T.  ORCID: https://orcid.org/0000-0003-3344-5877, Hostachy, S. ORCID: https://orcid.org/0000-0003-1867-9763, Dornan, G.L. ORCID: https://orcid.org/0000-0002-5170-9015, Neuenschwander, M. ORCID: https://orcid.org/0000-0002-3114-7975, Seyffarth, C., Haucke, V. ORCID: https://orcid.org/0000-0003-3119-6993, Schütz, A. ORCID: https://orcid.org/0000-0002-0606-2574, von Kries, J.P. ORCID: https://orcid.org/0000-0003-4716-4988 and Fiedler, D. ORCID: https://orcid.org/0000-0002-0798-946X
|
| Abstract: | Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development of potent IP6K inhibitors is gaining momentum, a pharmacological tool to distinguish the mammalian isozymes is still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed a high-throughput screen to identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency and selectivity towards the unique valine gatekeeper mutants of IP6K1 and IP6K2, compared to the respective wild-type kinases. Biochemical validation experiments revealed an allosteric mechanism of action that was corroborated by HDX-MS measurements. The latter analysis suggested that displacement of the αC helix, caused by the gatekeeper mutation, facilitates the binding of FMP-201300 to an allosteric pocket adjacent to the ATP binding site. FMP-201300 therefore serves as a valuable springboard for the further development of compounds that can selectively target the three mammalian IP6Ks; either as analog-sensitive kinase inhibitors or as an allosteric lead compound for the wild-type kinases. |
| Keywords: | Inositol Phosphates, Phosphotransferases (Phosphate Group Acceptor), Phytic Acid, Animals, Mammals |
| Source: | eLife |
| Title of Book: | An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications |
| Volume: | 21 |
| Page Range: | RP88982 |
| Date: | 16 October 2023 |
| Official Publication: | https://doi.org/10.7554/eLife.88982.1 |
| PubMed: | View item in PubMed |
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