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}
}
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 -