6CN2

Crystal structure of zebrafish Phosphatidylinositol-4-phosphate 5- kinase alpha isoform D236N with bound ATP/Ca2+

6CN2 の概要

• エントリーDOI: 10.2210/pdb6cn2/pdb
• 分子名称: Phosphatidylinositol-4-phosphate 5-kinase, type I, alpha, ADENOSINE-5'-TRIPHOSPHATE, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: pip5ka, atp, d236n, transferase
• 由来する生物種: Danio rerio (Zebrafish)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45455.66

構造登録者

Zeng, X.,Sui, D.,Hu, J. (登録日: 2018-03-07, 公開日: 2018-03-21, 最終更新日: 2023-10-04)

主引用文献

Zeng, X.,Uyar, A.,Sui, D.,Donyapour, N.,Wu, D.,Dickson, A.,Hu, J.
Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5K gamma.
Biochem. J., 475:2257-2269, 2018

PubMed Abstract: Signaling molecule phosphatidylinositol 4,5-bisphosphate is produced primarily by phosphatidylinositol 4-phosphate 5-kinase (PIP5K). PIP5K is essential for the development of the human neuronal system, which has been exemplified by a recessive genetic disorder, lethal congenital contractural syndrome type 3, caused by a single aspartate-to-asparagine mutation in the kinase domain of PIP5Kγ. So far, the exact role of this aspartate residue has yet to be elucidated. In this work, we conducted structural, functional and computational studies on a zebrafish PIP5Kα variant with a mutation at the same site. Compared with the structure of the wild-type (WT) protein in the ATP-bound state, the ATP-associating glycine-rich loop of the mutant protein was severely disordered and the temperature factor of ATP was significantly higher. Both observations suggest a greater degree of disorder of the bound ATP, whereas neither the structure of the catalytic site nor the toward ATP was substantially affected by the mutation. Microsecond molecular dynamics simulation revealed that negative charge elimination caused by the mutation destabilized the involved hydrogen bonds and affected key electrostatic interactions in the close proximity of ATP. Taken together, our data indicated that the disease-related aspartate residue is a key node in the interaction network crucial for effective ATP binding. This work provides a paradigm of how a subtle but critical structural perturbation caused by a single mutation at the ATP-binding site abolishes the kinase activity, emphasizing that stabilizing substrate in a productive conformational state is crucial for catalysis.

PubMed: 29959184
DOI: 10.1042/BCJ20180326

実験手法

X-RAY DIFFRACTION (3.102 Å)