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Structure, mechanism, and inhibition of Hedgehog acyltransferase.

Molecular cell (2021-12-11)
Claire E Coupland, Sebastian A Andrei, T Bertie Ansell, Loic Carrique, Pramod Kumar, Lea Sefer, Rebekka A Schwab, Eamon F X Byrne, Els Pardon, Jan Steyaert, Anthony I Magee, Thomas Lanyon-Hogg, Mark S P Sansom, Edward W Tate, Christian Siebold
ABSTRACT

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.

MATERIALS
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Brand
Product Description

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