6YK1

Crystal structure of mouse pyridoxal kinase in complex with ATP-gamma-S and artesunate

6YK1 の概要

• エントリーDOI: 10.2210/pdb6yk1/pdb
• 分子名称: Pyridoxal kinase, GLYCEROL, TETRAETHYLENE GLYCOL, ... (7 entities in total)
• 機能のキーワード: pdxk, plp, pl, vitamin b6, enzyme, artemisinin, artesunate, transferase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 145687.39

構造登録者

Kasaragod, V.B.,Schindelin, H. (登録日: 2020-04-05, 公開日: 2021-04-14, 最終更新日: 2024-01-24)

主引用文献

Kasaragod, V.B.,Pacios-Michelena, A.,Schaefer, N.,Zheng, F.,Bader, N.,Alzheimer, C.,Villmann, C.,Schindelin, H.
Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission.
Proc.Natl.Acad.Sci.USA, 117:33235-33245, 2020

PubMed Abstract: The antimalarial artemisinins have also been implicated in the regulation of various cellular pathways including immunomodulation of cancers and regulation of pancreatic cell signaling in mammals. Despite their widespread application, the cellular specificities and molecular mechanisms of target recognition by artemisinins remain poorly characterized. We recently demonstrated how these drugs modulate inhibitory postsynaptic signaling by direct binding to the postsynaptic scaffolding protein gephyrin. Here, we report the crystal structure of the central metabolic enzyme pyridoxal kinase (PDXK), which catalyzes the production of the active form of vitamin B6 (also known as pyridoxal 5'-phosphate [PLP]), in complex with artesunate at 2.4-Å resolution. Partially overlapping binding of artemisinins with the substrate pyridoxal inhibits PLP biosynthesis as demonstrated by kinetic measurements. Electrophysiological recordings from hippocampal slices and activity measurements of glutamic acid decarboxylase (GAD), a PLP-dependent enzyme synthesizing the neurotransmitter γ-aminobutyric acid (GABA), define how artemisinins also interfere presynaptically with GABAergic signaling. Our data provide a comprehensive picture of artemisinin-induced effects on inhibitory signaling in the brain.

PubMed: 33318193
DOI: 10.1073/pnas.2008695117

実験手法

X-RAY DIFFRACTION (2.4 Å)