8PPB

Human inositol 1,4,5-trisphosphate 3-kinase A (IP3K) catalytic domain in complex with D-3-deoxy-myo-inositol 1,4,6-trisphosphate/ATP/Mn

8PPB の概要

• エントリーDOI: 10.2210/pdb8ppb/pdb
• 関連するPDBエントリー: 8PP8 8PP9 8PPA
• 分子名称: Inositol-trisphosphate 3-kinase A, D-3-deoxy-myo-inositol 1,4,6-trisphosphate, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: inositol polyphosphate, insp, inositol kinase, ip3k, calcium, insp3, ip3, ipk, ip3 3-k, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66373.22

構造登録者

Marquez-Monino, M.A.,Gonzalez, B. (登録日: 2023-07-07, 公開日: 2024-02-28, 最終更新日: 2024-03-27)

主引用文献

Marquez-Monino, M.A.,Ortega-Garcia, R.,Whitfield, H.,Riley, A.M.,Infantes, L.,Garrett, S.W.,Shipton, M.L.,Brearley, C.A.,Potter, B.V.L.,Gonzalez, B.
Substrate promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity.
Nat Commun, 15:1502-1502, 2024

PubMed Abstract: D-myo-inositol 1,4,5-trisphosphate (InsP) is a fundamental second messenger in cellular Ca mobilization. InsP 3-kinase, a highly specific enzyme binding InsP in just one mode, phosphorylates InsP specifically at its secondary 3-hydroxyl group to generate a tetrakisphosphate. Using a chemical biology approach with both synthetised and established ligands, combining synthesis, crystallography, computational docking, HPLC and fluorescence polarization binding assays using fluorescently-tagged InsP, we have surveyed the limits of InsP 3-kinase ligand specificity and uncovered surprisingly unforeseen biosynthetic capacity. Structurally-modified ligands exploit active site plasticity generating a helix-tilt. These facilitated uncovering of unexpected substrates phosphorylated at a surrogate extended primary hydroxyl at the inositol pseudo 3-position, applicable even to carbohydrate-based substrates. Crystallization experiments designed to allow reactions to proceed in situ facilitated unequivocal characterization of the atypical tetrakisphosphate products. In summary, we define features of InsP 3-kinase plasticity and substrate tolerance that may be more widely exploitable.

PubMed: 38374076
DOI: 10.1038/s41467-024-45917-5

実験手法

X-RAY DIFFRACTION (1.8 Å)