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Citation

BibTex format

@article{Lanyon-Hogg:2021:10.1101/2020.10.16.342477,
author = {Lanyon-Hogg, T and Ritzefeld, M and Zhang, L and Pogranyi, B and Mondal, M and Sefer, L and Johnston, CD and Coupland, CE and Andrei, SA and Newington, J and Magee, AI and Siebold, C and Tate, EW},
doi = {10.1101/2020.10.16.342477},
journal = {Angewandte Chemie International Edition},
pages = {13542--13547},
title = {Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound O-acyltransferase},
url = {http://dx.doi.org/10.1101/2020.10.16.342477},
volume = {60},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The mammalian membranebound 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 smallmolecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel smallmolecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structureactivity relationship investigation identified single enantiomer IMP1575 , the most potent HHAT inhibitor reported todate, and guided design of photocrosslinking probes that maintained HHATinhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first smallmolecule 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 IMP1575 ( K i  = 38 nM) and a strategy for mapping small molecule interaction sites in MBOATs.
AU  - Lanyon-Hogg,T
AU  - Ritzefeld,M
AU  - Zhang,L
AU  - Pogranyi,B
AU  - Mondal,M
AU  - Sefer,L
AU  - Johnston,CD
AU  - Coupland,CE
AU  - Andrei,SA
AU  - Newington,J
AU  - Magee,AI
AU  - Siebold,C
AU  - Tate,EW
DO  - 10.1101/2020.10.16.342477
EP  - 13547
PY  - 2021///
SN  - 1433-7851
SP  - 13542
TI  - Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound O-acyltransferase
T2  - Angewandte Chemie International Edition
UR  - http://dx.doi.org/10.1101/2020.10.16.342477
UR  - https://onlinelibrary.wiley.com/doi/10.1002/anie.202014457
UR  - http://hdl.handle.net/10044/1/87627
VL  - 60
ER  -
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Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821