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Structural characterisation of melatonin as an inhibitor of the Wnt deacylase Notum

DOI: 10.1111/jpi.12630 DOI Help

Authors: Yuguang Zhao (Wellcome Centre for Human Genetics, University of Oxford) , Jingshan Ren (Wellcome Centre for Human Genetics, University of Oxford) , James Hillier (Wellcome Centre for Human Genetics, University of Oxford) , Margaret Jones (Wellcome Centre for Human Genetics, University of Oxford) , Weixian Lu (Wellcome Centre for Human Genetics, University of Oxford) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Pineal Research

State: Published (Approved)
Published: December 2019
Diamond Proposal Number(s): 16814 , 14744

Abstract: The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β-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 Å) 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 µM), 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.

Journal Keywords: Notum; Wnt signalling; crystal structure; fragment screen; melatonin

Diamond Keywords: Alzheimer's Disease; Enzymes

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 08/01/2020 11:26

Discipline Tags:

Osteoporosis Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening