Imperial College London
Alternate

Emeritus ProfessorTonyMagee

Faculty of Medicine, National Heart & Lung Institute

Emeritus Professor of Membrane Biology
 
 
 
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Contact

 

t.magee Website

 
 
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Location

 

Office no. 115Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@unpublished{Lanyon-Hogg:2020:10.1101/2020.10.16.342477,
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},
title = {Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound <i>O</i>-acyltransferase},
url = {http://dx.doi.org/10.1101/2020.10.16.342477},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - UNPB
AB  - <jats:title>Abstract</jats:title><jats:p>The mammalian membrane-bound <jats:italic>O</jats:italic>-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 development of a photochemical probe to interrogate the small-molecule binding site in the human MBOAT Hedgehog acyltransferase (HHAT) based on HHAT inhibitor RUSKI-201. Structure-activity relationship investigation identified the improved enantiomeric inhibitor <jats:bold>IMP-1575</jats:bold>, which is the most potent HHAT inhibitor reported to-date, and guided rational design of a photocrosslinking probe 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 inhibitor <jats:bold>IMP-1575</jats:bold> (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> = 38 nM) and a strategy for mapping of interaction sites in MBOATs.</jats:p>
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
PY  - 2020///
TI  - Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound <i>O</i>-acyltransferase
UR  - http://dx.doi.org/10.1101/2020.10.16.342477
ER  -
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