7Q1U

Structure of Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to non-hydrolysable palmitoyl-CoA (Composite Map)

7Q1U の概要

• エントリーDOI: 10.2210/pdb7q1u/pdb
• 関連するPDBエントリー: 7Q1U
• EMDBエントリー: 13764 13841 13842 14578
• 分子名称: Protein-cysteine N-palmitoyltransferase HHAT, Megabody 177, CHOLESTEROL, ... (7 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 163700.00

構造登録者

Coupland, C.,Carrique, L.,Siebold, C. (登録日: 2021-10-21, 公開日: 2022-06-08)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (2.7 Å)