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

@article{Coupland:2021:10.1016/j.molcel.2021.11.018,
author = {Coupland, CE and Andrei, SA and Ansell, TB and Carrique, L and Kumar, P and Sefer, L and Schwab, RA and Byrne, EFX and Pardon, E and Steyaert, J and Magee, A and Lanyon-Hogg, T and Sansom, MSP and Tate, EW and Siebold, C},
doi = {10.1016/j.molcel.2021.11.018},
journal = {Molecular Cell},
pages = {5025--+},
title = {Structure, mechanism, and inhibition of Hedgehog acyltransferase},
url = {http://dx.doi.org/10.1016/j.molcel.2021.11.018},
volume = {81},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery.
AU  - Coupland,CE
AU  - Andrei,SA
AU  - Ansell,TB
AU  - Carrique,L
AU  - Kumar,P
AU  - Sefer,L
AU  - Schwab,RA
AU  - Byrne,EFX
AU  - Pardon,E
AU  - Steyaert,J
AU  - Magee,A
AU  - Lanyon-Hogg,T
AU  - Sansom,MSP
AU  - Tate,EW
AU  - Siebold,C
DO  - 10.1016/j.molcel.2021.11.018
EP  - 5025
PY  - 2021///
SN  - 1097-2765
SP  - 5025
TI  - Structure, mechanism, and inhibition of Hedgehog acyltransferase
T2  - Molecular Cell
UR  - http://dx.doi.org/10.1016/j.molcel.2021.11.018
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000733707000009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00998-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276521009989%3Fshowall%3Dtrue
UR  - http://hdl.handle.net/10044/1/95075
VL  - 81
ER  -
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