6NYV

Structure of spastin AAA domain in complex with a quinazoline-based inhibitor

6NYV の概要

• エントリーDOI: 10.2210/pdb6nyv/pdb
• 関連するPDBエントリー: 6NYW
• 分子名称: Spastin, SULFATE ION, N-(3-tert-butyl-1H-pyrazol-5-yl)-2-[(2R)-2-methylpiperazin-1-yl]quinazolin-4-amine, ... (5 entities in total)
• 機能のキーワード: aaa+ protein, atpase, hydrolase, enzyme-inhibitor complex, isomerase-inhibitor complex, isomerase/inhibitor
• 由来する生物種: Drosophila melanogaster (Fruit fly)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34900.74

構造登録者

Pisa, R.,Cupido, T.,Kapoor, T.M. (登録日: 2019-02-12, 公開日: 2019-03-27, 最終更新日: 2023-10-11)

主引用文献

Pisa, R.,Cupido, T.,Kapoor, T.M.
Designing Allele-Specific Inhibitors of Spastin, a Microtubule-Severing AAA Protein.
J. Am. Chem. Soc., 141:5602-5606, 2019

PubMed Abstract: The bump-hole approach is a powerful chemical biology strategy to specifically probe the functions of closely related proteins. However, for many protein families, such as the ATPases associated with diverse cellular activities (AAA), we lack structural data for inhibitor-protein complexes to design allele-specific chemical probes. Here we report the X-ray structure of a pyrazolylaminoquinazoline-based inhibitor bound to spastin, a microtubule-severing AAA protein, and characterize the residues involved in inhibitor binding. We show that an inhibitor analogue with a single-atom hydrogen-to-fluorine modification can selectively target a spastin allele with an engineered cysteine mutation in its active site. We also report an X-ray structure of the fluoro analogue bound to the spastin mutant. Furthermore, analyses of other mutant alleles suggest how the stereoelectronics of the fluorine-cysteine interaction, rather than sterics alone, contribute to the inhibitor-allele selectivity. This approach could be used to design allele-specific probes for studying cellular functions of spastin isoforms. Our data also suggest how tuning stereoelectronics can lead to specific inhibitor-allele pairs for the AAA superfamily.

PubMed: 30875216
DOI: 10.1021/jacs.8b13257

実験手法

X-RAY DIFFRACTION (2.425 Å)