9OO7

Human PORCN bound to inhibitor ETC159

これはPDB形式変換不可エントリーです。

9OO7 の概要

• エントリーDOI: 10.2210/pdb9oo7/pdb
• 関連するPDBエントリー: 9OO6
• EMDBエントリー: 70661
• 分子名称: Isoform 3 of Protein-serine O-palmitoleoyltransferase porcupine,Green fluorescent protein, ZINC ION, 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(6-phenylpyridazin-3-yl)acetamide, ... (4 entities in total)
• 機能のキーワード: transmembrane protein, mboat, acylase, wnt acylase, enzyme, er, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 82215.14

構造登録者

Black, K.A.,Venugopal, H.,Glukhova, A. (登録日: 2025-05-15, 公開日: 2025-12-10)

主引用文献

Black, K.A.,Mobbs, J.I.,Venugopal, H.,Dite, T.A.,Leis, A.,Wong, L.L.,Dagley, L.F.,Thal, D.M.,Glukhova, A.
Structural basis for Porcupine inhibition.
Commun Chem, 8:348-348, 2025

PubMed Abstract: Wnt signalling is essential for embryonic development and tissue homeostasis, and its dysregulation is associated with multiple types of cancer. Porcupine (PORCN), an endoplasmic reticulum (ER)-resident membrane-bound O-acyltransferase, catalyses the palmitoleoylation of all 19 human Wnts-a critical modification required for their secretion and activity. This central role makes PORCN an attractive therapeutic target for Wnt-driven cancers, with several inhibitors currently in clinical trials. Here, we present high-resolution cryo-electron microscopy structures of human PORCN in complex with the inhibitors C59 (2.4 Å) and ETC159 (2.6 Å), as well as in a ligand-free state (3.3 Å). These structures reveal critical ordered water molecules that form a hydrogen-bonding network within the active site, mediating inhibitor binding. Our docking simulations of diverse PORCN inhibitors demonstrate that despite their different chemical scaffolds, these compounds adopt similar conformations within the acyl-CoA binding site and are also engaged through a conserved water molecule. Our findings provide a structural foundation for the rational design of next-generation PORCN inhibitors with improved pharmacological properties for cancer therapy.

PubMed: 41225132
DOI: 10.1038/s42004-025-01726-5

実験手法

ELECTRON MICROSCOPY (2.61 Å)