7L9X

Structure of VPS4B in complex with an allele-specific covalent inhibitor

7L9X の概要

• エントリーDOI: 10.2210/pdb7l9x/pdb
• 分子名称: Vacuolar protein sorting-associated protein 4B, N-{3-[(8-phenyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]phenyl}propanamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: chemical inhibitor, hydrolase, atpase, aaa superfamily, protein transport
• 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: 50039.73

構造登録者

Grasso, M.,Cupido, T.,Kapoor, T.M. (登録日: 2021-01-05, 公開日: 2021-04-14, 最終更新日: 2024-10-30)

主引用文献

Cupido, T.,Jones, N.H.,Grasso, M.J.,Pisa, R.,Kapoor, T.M.
A chemical genetics approach to examine the functions of AAA proteins.
Nat.Struct.Mol.Biol., 28:388-397, 2021

PubMed Abstract: The structural conservation across the AAA (ATPases associated with diverse cellular activities) protein family makes designing selective chemical inhibitors challenging. Here, we identify a triazolopyridine-based fragment that binds the AAA domain of human katanin, a microtubule-severing protein. We have developed a model for compound binding and designed ASPIR-1 (allele-specific, proximity-induced reactivity-based inhibitor-1), a cell-permeable compound that selectively inhibits katanin with an engineered cysteine mutation. Only in cells expressing mutant katanin does ASPIR-1 treatment increase the accumulation of CAMSAP2 at microtubule minus ends, confirming specific on-target cellular activity. Importantly, ASPIR-1 also selectively inhibits engineered cysteine mutants of human VPS4B and FIGL1-AAA proteins, involved in organelle dynamics and genome stability, respectively. Structural studies confirm our model for compound binding at the AAA ATPase site and the proximity-induced reactivity-based inhibition. Together, our findings suggest a chemical genetics approach to decipher AAA protein functions across essential cellular processes and to test hypotheses for developing therapeutics.

PubMed: 33782614
DOI: 10.1038/s41594-021-00575-9

実験手法

X-RAY DIFFRACTION (2.81 Å)