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Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound O-acyltransferase

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Title: Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound O-acyltransferase
Authors: Lanyon-Hogg, T
Ritzefeld, M
Zhang, L
Pogranyi, B
Mondal, M
Sefer, L
Johnston, CD
Coupland, CE
Andrei, SA
Newington, J
Magee, AI
Siebold, C
Tate, EW
Item Type: Journal Article
Abstract: The mammalian membrane‐bound O ‐acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small‐molecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel small‐molecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structure‐activity relationship investigation identified single enantiomer IMP‐1575 , the most potent HHAT inhibitor reported to‐date, and guided design of photocrosslinking probes that maintained HHAT‐inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small‐molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed via kinetic analysis. Our results provide an optimal HHAT tool inhibitor IMP‐1575 ( K i = 38 nM) and a strategy for mapping small molecule interaction sites in MBOATs.
Issue Date: 7-Jun-2021
Date of Acceptance: 24-Mar-2021
URI: http://hdl.handle.net/10044/1/87627
DOI: 10.1101/2020.10.16.342477
ISSN: 1433-7851
Publisher: Wiley
Start Page: 13542
End Page: 13547
Journal / Book Title: Angewandte Chemie International Edition
Volume: 60
Issue: 24
Copyright Statement: © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Cancer Research UK
Biotechnology and Biological Sciences Research Council (BBSRC)
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: 20183
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Hedgehog acyltransferase
Hedgehog signalling
membrane-bound O-acyltransferase
photoaffinity labelling
Hedgehog acyltransferase
Hedgehog signalling
membrane-bound O-acyltransferase
photoaffinity labelling
Organic Chemistry
03 Chemical Sciences
Publication Status: Published
Online Publication Date: 2021-03-26
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
National Heart and Lung Institute
Faculty of Medicine
Faculty of Natural Sciences

This item is licensed under a Creative Commons License Creative Commons