Zhao_2019_J.Pineal.Res__e12630

Reference

Title : Structural characterisation of melatonin as an inhibitor of the Wnt deacylase Notum - Zhao_2019_J.Pineal.Res__e12630
Author(s) : Zhao Y , Ren J , Hillier J , Jones M , Lu W , Jones EY
Ref : J Pineal Res , :e12630 , 2019
Abstract :

The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/beta-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin, came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high resolution structures (<= 1.5 A) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid; and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 microM), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which up-regulation of Wnt signalling may be beneficial.

PubMedSearch : Zhao_2019_J.Pineal.Res__e12630
PubMedID: 31876313
Gene_locus related to this paper: human-NOTUM

Citations formats

Zhao Y, Ren J, Hillier J, Jones M, Lu W, Jones EY (2019)
Structural characterisation of melatonin as an inhibitor of the Wnt deacylase Notum
J Pineal Res :e12630

Zhao Y, Ren J, Hillier J, Jones M, Lu W, Jones EY (2019)
J Pineal Res :e12630