6YUY

STRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A PYRROLE-3-CARBOXYLIC ACID FRAGMENT 471

6YUY の概要

• エントリーDOI: 10.2210/pdb6yuy/pdb
• 分子名称: Palmitoleoyl-protein carboxylesterase NOTUM, SULFATE ION, DIMETHYL SULFOXIDE, ... (6 entities in total)
• 機能のキーワード: wnt, wnt signalling, frizzled, fzd, fragment screen, notum, hydrolase
• 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: 45596.62

構造登録者

Hillier, J.,Ruza, R.R.,Jones, E.Y. (登録日: 2020-04-27, 公開日: 2020-05-06, 最終更新日: 2024-10-16)

主引用文献

Mahy, W.,Patel, M.,Steadman, D.,Woodward, H.L.,Atkinson, B.N.,Svensson, F.,Willis, N.J.,Flint, A.,Papatheodorou, D.,Zhao, Y.,Vecchia, L.,Ruza, R.R.,Hillier, J.,Frew, S.,Monaghan, A.,Costa, A.,Bictash, M.,Walter, M.W.,Jones, E.Y.,Fish, P.V.
Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity.
J.Med.Chem., 63:9464-9483, 2020

PubMed Abstract: The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole , guided by structure-based drug design, identified as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine gave acid . This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable ADME profiles.

PubMed: 32787107
DOI: 10.1021/acs.jmedchem.0c00660

実験手法

X-RAY DIFFRACTION (2 Å)