9DN3

Crystal Structure of Human Inositol 1,3,4-Trisphosphate 5/6-kinase (ITPK1) in Complex with an Inhibitor 9-cylcopentyladenine

これはPDB形式変換不可エントリーです。

9DN3 の概要

• エントリーDOI: 10.2210/pdb9dn3/pdb
• 分子名称: Inositol-tetrakisphosphate 1-kinase, SULFATE ION, 9-cyclopentyl-9H-purin-6-amine, ... (4 entities in total)
• 機能のキーワード: inhibitor development, inositol phosphate kinase, inhibitor complex, cancer therapy, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37603.75

構造登録者

Wang, H. (登録日: 2024-09-16, 公開日: 2025-02-19, 最終更新日: 2025-03-19)

主引用文献

Ng, M.Y.,Wang, H.,Zhang, H.,Prucker, I.,Perera, L.,Goncharova, E.,Wamiru, A.,Jessen, H.J.,Stanley, R.E.,Shears, S.B.,Luo, J.,O'Keefe, B.R.,Wilson, B.A.P.
Biochemical and biophysical characterization of inositol-tetrakisphosphate 1-kinase inhibitors.
J.Biol.Chem., 301:108274-108274, 2025

PubMed Abstract: Inositol phosphates (IPs) and inositol pyrophosphate play critical roles in many biological processes such 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) and inositol-3,4,5,6-tetrakisphosphate (IP), generating inositol-1,3,4,5,6-pentakisphosphate (IP), which can be further phosphorylated to become inositol hexakisphosphate (IP). ITPK1 also possesses phosphatase activity that can convert IP back to IP; therefore, ITPK1 may serve as a regulatory step in IP production. IP 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 Å. This work provides insight into the design of potential next-generation inhibitors.

PubMed: 39922495
DOI: 10.1016/j.jbc.2025.108274

実験手法

X-RAY DIFFRACTION (2.25 Å)