6YXI
Structure of Notum in complex with a 1-(3-Chlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid inhibitor
Summary for 6YXI
| Entry DOI | 10.2210/pdb6yxi/pdb |
| Descriptor | Palmitoleoyl-protein carboxylesterase NOTUM, 1-(3-chlorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic acid, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total) |
| Functional Keywords | inhibitor, complex, wnt pathway, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 44912.76 |
| Authors | Vecchia, L.,Jones, E.Y.,Ruza, R.R.,Hillier, J.,Zhao, Y. (deposition date: 2020-05-01, release date: 2020-08-19, Last modification date: 2024-11-06) |
| Primary citation | 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 Cited by 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: 32787107DOI: 10.1021/acs.jmedchem.0c00660 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.34 Å) |
Structure validation
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