6P12

Structure of spastin AAA domain (wild-type) in complex with diaminotriazole-based inhibitor

6P12 の概要

• エントリーDOI: 10.2210/pdb6p12/pdb
• 分子名称: Drosophila melanogaster Spastin AAA domain, 3-{[5-amino-1-(2-fluoro-6-methoxybenzene-1-carbonyl)-1H-1,2,4-triazol-3-yl]amino}-N-methylbenzamide, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, aaa protein, isomerase-isomerase inhibitor complex, isomerase/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: 34790.45

構造登録者

Pisa, R.,Cupido, T.,Kapoor, T.M. (登録日: 2019-05-17, 公開日: 2019-07-24, 最終更新日: 2023-10-11)

主引用文献

Pisa, R.,Cupido, T.,Steinman, J.B.,Jones, N.H.,Kapoor, T.M.
Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins.
Cell Chem Biol, 26:1263-, 2019

PubMed Abstract: Drug-like inhibitors are often designed by mimicking cofactor or substrate interactions with enzymes. However, as active sites are comprised of conserved residues, it is difficult to identify the critical interactions needed to design selective inhibitors. We are developing an approach, named RADD (resistance analysis during design), which involves engineering point mutations in the target to generate active alleles and testing compounds against them. Mutations that alter compound potency identify residues that make key interactions with the inhibitor and predict target-binding poses. Here, we apply this approach to analyze how diaminotriazole-based inhibitors bind spastin, a microtubule-severing AAA (ATPase associated with diverse cellular activities) protein. The distinct binding poses predicted for two similar inhibitors were confirmed by a series of X-ray structures. Importantly, our approach not only reveals how selective inhibition of the target can be achieved but also identifies resistance-conferring mutations at the early stages of the design process.

PubMed: 31257183
DOI: 10.1016/j.chembiol.2019.06.001

実験手法

X-RAY DIFFRACTION (1.9413185678 Å)