5VSB

Structure of DUB complex

5VSB の概要

• エントリーDOI: 10.2210/pdb5vsb/pdb
• 関連するPDBエントリー: 5VS6
• 分子名称: Ubiquitin carboxyl-terminal hydrolase 7, 7-chloro-3-{[4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl]methyl}quinazolin-4(3H)-one (3 entities in total)
• 機能のキーワード: deubiquitinase, inhibitor, protein-inhibitor complex, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q93009
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82860.50

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2017-05-11, 公開日: 2017-12-20, 最終更新日: 2024-03-13)

主引用文献

Lamberto, I.,Liu, X.,Seo, H.S.,Schauer, N.J.,Iacob, R.E.,Hu, W.,Das, D.,Mikhailova, T.,Weisberg, E.L.,Engen, J.R.,Anderson, K.C.,Chauhan, D.,Dhe-Paganon, S.,Buhrlage, S.J.
Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7.
Cell Chem Biol, 24:1490-1500.e11, 2017

PubMed Abstract: Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5-10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high-resolution DUB⋅small-molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small-molecule⋅ubiquitin-specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are non-covalent active-site inhibitors.

PubMed: 29056421
DOI: 10.1016/j.chembiol.2017.09.003

実験手法

X-RAY DIFFRACTION (1.85 Å)