9dn3
From Proteopedia
Crystal Structure of Human Inositol 1,3,4-Trisphosphate 5/6-kinase (ITPK1) in Complex with an Inhibitor 9-cylcopentyladenine
Structural highlights
FunctionITPK1_HUMAN Kinase that can phosphorylate various inositol polyphosphate such as Ins(3,4,5,6)P4 or Ins(1,3,4)P3. Phosphorylates Ins(3,4,5,6)P4 at position 1 to form Ins(1,3,4,5,6)P5. This reaction is thought to have regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca(2+)-activated Cl(-) channels, while Ins(1,3,4,5,6)P5 is not. Also phosphorylates Ins(1,3,4)P3 on O-5 and O-6 to form Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway. Also acts as an inositol polyphosphate phosphatase that dephosphorylate Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 to Ins(1,3,4)P3, and Ins(1,3,4,5,6)P5 to Ins(3,4,5,6)P4. May also act as an isomerase that interconverts the inositol tetrakisphosphate isomers Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 in the presence of ADP and magnesium. Probably acts as the rate-limiting enzyme of the InsP6 pathway. Modifies TNF-alpha-induced apoptosis by interfering with the activation of TNFRSF1A-associated death domain.[1] [2] [3] [4] Publication Abstract from PubMedInositol phosphates (IPs) and inositol pyrophosphate play critical roles in many biological processes as signaling molecules in pathways responsible for cellular functions involved in growth and maintenance. The biosynthesis of IPs is carried out by a family of inositol phosphate kinases. In mammals, Inositol tetrakisphosphate kinase-1 (ITPK1) phosphorylates inositol-1,3,4-trisphosphate (Ins(1,3,4)P(3)) and inositol-3,4,5,6-tetrakisphosphate (IP(4)), generating inositol-1,3,4,5,6-pentakisphosphate (IP(5)), which can be further phosphorylated to become inositol hexakisphosphate (IP(6)). ITPK1 also possesses phosphatase activity that can convert IP(5) back to IP(4); therefore, ITPK1 may serve as a regulatory step in IP(6) production. IP(6) utilization has been implicated in processes fundamental to cellular sustainability that are severely perturbed in many disease states including RNA editing, DNA repair, chromatin structure organization, and ubiquitin ligation. Therefore, ITPK1, with no known inhibitors in the literature, is a potential molecular target for modulating important processes in several human diseases. By independently coupling ITPK1 phosphatase and kinase activities to luciferase activity, we have developed and used biochemical high throughput assays to discover eight ITPK1 inhibitors. Further analysis revealed that three of these leads inhibit ITPK1 in an ATP-competitive manner, with low micromolar to nanomolar affinities. We further demonstrate that the most potent ITPK1 inhibitor can regulate cellular ITPK1 activity. We determined the crystal structure of ITPK1 in complex with this inhibitor at a resolution of 2.25 A. This work provides insight into the design of potential next-generation inhibitors. Biochemical and biophysical characterization of inositol-tetrakisphosphate 1-kinase inhibitors.,Ng MY, Wang H, Zhang H, Prucker I, Perera L, Goncharova E, Wamiru A, Jessen HJ, Stanley RE, Shears SB, Luo J, O'Keefe BR, Wilson BAP J Biol Chem. 2025 Feb 6:108274. doi: 10.1016/j.jbc.2025.108274. PMID:39922495[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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