7B37

Notum complex with ARUK3003718

Summary for 7B37

• Entry DOI: 10.2210/pdb7b37/pdb
• Descriptor: Palmitoleoyl-protein carboxylesterase NOTUM, 2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (7 entities in total)
• Functional Keywords: notum inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 44750.38

Authors

Zhao, Y.,Jone, E.Y. (deposition date: 2020-11-28, release date: 2021-08-04, Last modification date: 2024-11-13)

Primary citation

Zhao, Y.,Svensson, F.,Steadman, D.,Frew, S.,Monaghan, A.,Bictash, M.,Moreira, T.,Chalk, R.,Lu, W.,Fish, P.V.,Jones, E.Y.
Structural Insights into Notum Covalent Inhibition.
J.Med.Chem., 64:11354-11363, 2021

PubMed Abstract: The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer's disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors.

PubMed: 34292747
DOI: 10.1021/acs.jmedchem.1c00701

Experimental method

X-RAY DIFFRACTION (1.34 Å)