8OMI

Crystal structure of the inositol hexakisphosphate kinase EhIP6KA M85 variant in complex with ATP and Mg2+

Summary for 8OMI

• Entry DOI: 10.2210/pdb8omi/pdb
• Descriptor: Kinase, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: complex, transferase
• Biological source: Entamoeba histolytica
• Total number of polymer chains: 1
• Total formula weight: 30068.54

Authors

Schuetz, A.,Aguirre, T.,Fiedler, D. (deposition date: 2023-03-31, release date: 2024-01-10)

Primary citation

Aguirre, T.,Dornan, G.L.,Hostachy, S.,Neuenschwander, M.,Seyffarth, C.,Haucke, V.,Schutz, A.,von Kries, J.P.,Fiedler, D.
An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor.
Elife, 12:-, 2023

PubMed 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 toward the unique valine gatekeeper mutants of IP6K1 and IP6K2, compared to the respective wild-type (WT) kinases. Biochemical validation experiments revealed an allosteric mechanism of action that was corroborated by hydrogen deuterium exchange mass spectrometry measurements. The latter analysis suggested that displacement of the C 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 WT kinases.

PubMed: 37843983
DOI: 10.7554/eLife.88982

Experimental method

X-RAY DIFFRACTION (1.77 Å)