EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Mechanisms and inhibition of Porcupine-mediated Wnt acylation.
ジャーナル・号・ページ	Nature, Vol. 607, Issue 7920, Page 816-822, Year 2022
掲載日	2022年7月13日
著者	Yang Liu / Xiaofeng Qi / Linda Donnelly / Nadia Elghobashi-Meinhardt / Tao Long / Rich W Zhou / Yingyuan Sun / Boyuan Wang / Xiaochun Li /
PubMed 要旨	Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt signalling requires ...Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling. Here we report four cryo-electron microscopy structures of human PORCN: the complex with the palmitoleoyl-coenzyme A (palmitoleoyl-CoA) substrate; the complex with the PORCN inhibitor LGK974, an anti-cancer drug currently in clinical trials; the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex with a synthetic palmitoleoylated WNT3Ap analogue. The structures reveal that hairpin 2 of WNT3A, which is well conserved in all Wnt ligands, inserts into PORCN from the lumenal side, and the palmitoleoyl-CoA accesses the enzyme from the cytosolic side. The catalytic histidine triggers the transfer of the unsaturated palmitoleoyl group to the target serine on the Wnt hairpin 2, facilitated by the proximity of the two substrates. The inhibitor-bound structure shows that LGK974 occupies the palmitoleoyl-CoA binding site to prevent the reaction. Thus, this work provides a mechanism for Wnt acylation and advances the development of PORCN inhibitors for cancer treatment.
リンク	Nature / PubMed:35831507 / PubMed Central
手法	EM (単粒子)
解像度	2.8 - 3.19 Å
構造データ	26707 7ura EMDB-26707, PDB-7ura: Human PORCN in complex with Palmitoleoyl-CoA 手法: EM (単粒子) / 解像度: 3.11 Å 26708 7urc EMDB-26708, PDB-7urc: Human PORCN in complex with LGK974 手法: EM (単粒子) / 解像度: 3.14 Å 26709 7urd EMDB-26709, PDB-7urd: Human PORCN in complex with LGK974 and WNT3A peptide 手法: EM (単粒子) / 解像度: 2.92 Å 26710 7ure EMDB-26710, PDB-7ure: Human PORCN in complex with palmitoleoylated WNT3A peptide 手法: EM (単粒子) / 解像度: 3.19 Å 26711 7urf EMDB-26711, PDB-7urf: Human HHAT H379C in complex with SHH N-terminal peptide 手法: EM (単粒子) / 解像度: 2.8 Å
化合物	ChemComp-OH6: ~{S}-[2-[3-[[(2~{R})-4-[[[(2~{R},3~{R},4~{R},5~{R})-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl-butanoyl]amino]propanoylamino]ethyl] (~{Z})-hexadec-9-enethioate ChemComp-ZN: Unknown entry ChemComp-CLR: CHOLESTEROL / コレステロ-ル ChemComp-AJP: Digitonin / ジギトニン / 可溶化剤YM ChemComp-OLA: OLEIC ACID / オレイン酸 ChemComp-O50: 2-[(2P)-2',3-dimethyl[2,4'-bipyridin]-5-yl]-N-[(5P)-5-(pyrazin-2-yl)pyridin-2-yl]acetamide / LGK-974 ChemComp-PAM: PALMITOLEIC ACID / パルミトレイン酸 ChemComp-HEM: PROTOPORPHYRIN IX CONTAINING FE ChemComp-PKZ*: Palmitoyl-CoA / パルミトイルCoA
由来	homo sapiens (ヒト) mus musculus (ハツカネズミ)
キーワード	TRANSFERASE/TRANSFERASE INHIBITOR / CoA-bound / complex / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex / Inhibitor-bound / substrate-bound / product-bound / TRANSFERASE-TRANSFERASE PRODUCT complex / TRANSFERASE-TRANSFERASE SUBSTRATE complex