5WHC

USP7 in complex with Cpd2 (4-(3-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)phenol)

5WHC の概要

• エントリーDOI: 10.2210/pdb5whc/pdb
• 関連するPDBエントリー: 5WH7
• 分子名称: Ubiquitin carboxyl-terminal hydrolase 7, 4-[3-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl]phenol, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: hausp, sbdd, hydrolase
• 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: 80793.27

構造登録者

Murray, J.M.,Rouge, L. (登録日: 2017-07-16, 公開日: 2017-12-13, 最終更新日: 2023-10-04)

主引用文献

Di Lello, P.,Pastor, R.,Murray, J.M.,Blake, R.A.,Cohen, F.,Crawford, T.D.,Drobnick, J.,Drummond, J.,Kategaya, L.,Kleinheinz, T.,Maurer, T.,Rouge, L.,Zhao, X.,Wertz, I.,Ndubaku, C.,Tsui, V.
Discovery of Small-Molecule Inhibitors of Ubiquitin Specific Protease 7 (USP7) Using Integrated NMR and in Silico Techniques.
J. Med. Chem., 60:10056-10070, 2017

PubMed Abstract: USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53, and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical, and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)phenol compounds described by Kategaya ( Nature 2017 , 550 , 534 - 538 ) as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity. These ligands were then optimized by structure-based design to yield cell-active molecules with reasonable physical properties. This discovery process not only involved multiple techniques working in concert but also illustrated a unique way in which hits from orthogonal screening approaches complemented each other for lead identification.

PubMed: 29166018
DOI: 10.1021/acs.jmedchem.7b01293

実験手法

X-RAY DIFFRACTION (2.548 Å)