7Q6Z

Structure of Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to IMP-1575

Summary for 7Q6Z

• Entry DOI: 10.2210/pdb7q6z/pdb
• Related: 7Q1U
• EMDB information: 13764 13860
• Descriptor: Protein-cysteine N-palmitoyltransferase HHAT, Megabody 177, CHOLESTEROL, ... (6 entities in total)
• Functional Keywords: hhat, inhibitor, palmitoyl-coa, co enzyme a, hedgehog acyl transferase, sonic hedgehog, shh, mboat, morphogen, palmitoylation, signalling, endoplasmic reticulum, membrane protein, heme, small molecule binding, drug target
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 162532.39

Authors

Coupland, C.,Carrique, L.,Siebold, C. (deposition date: 2021-11-09, release date: 2022-01-26, Last modification date: 2024-11-20)

Primary citation

Coupland, C.E.,Andrei, S.A.,Ansell, T.B.,Carrique, L.,Kumar, P.,Sefer, L.,Schwab, R.A.,Byrne, E.F.X.,Pardon, E.,Steyaert, J.,Magee, A.I.,Lanyon-Hogg, T.,Sansom, M.S.P.,Tate, E.W.,Siebold, C.
Structure, mechanism, and inhibition of Hedgehog acyltransferase.
Mol.Cell, 81:5025-5038.e10, 2021

PubMed 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.

PubMed: 34890564
DOI: 10.1016/j.molcel.2021.11.018

Experimental method

ELECTRON MICROSCOPY (3.59 Å)