Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Mechanisms and inhibition of Porcupine-mediated Wnt acylation.
Journal, issue, pages	Nature, Vol. 607, Issue 7920, Page 816-822, Year 2022
Publish date	Jul 13, 2022
Authors	Yang Liu / Xiaofeng Qi / Linda Donnelly / Nadia Elghobashi-Meinhardt / Tao Long / Rich W Zhou / Yingyuan Sun / Boyuan Wang / Xiaochun Li /
PubMed Abstract	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.
External links	Nature / PubMed:35831507 / PubMed Central
Methods	EM (single particle)
Resolution	2.8 - 3.19 Å
Structure data	26707 7ura EMDB-26707, PDB-7ura: Human PORCN in complex with Palmitoleoyl-CoA Method: EM (single particle) / Resolution: 3.11 Å 26708 7urc EMDB-26708, PDB-7urc: Human PORCN in complex with LGK974 Method: EM (single particle) / Resolution: 3.14 Å 26709 7urd EMDB-26709, PDB-7urd: Human PORCN in complex with LGK974 and WNT3A peptide Method: EM (single particle) / Resolution: 2.92 Å 26710 7ure EMDB-26710, PDB-7ure: Human PORCN in complex with palmitoleoylated WNT3A peptide Method: EM (single particle) / Resolution: 3.19 Å 26711 7urf EMDB-26711, PDB-7urf: Human HHAT H379C in complex with SHH N-terminal peptide Method: EM (single particle) / Resolution: 2.8 Å
Chemicals	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 / Cholesterol ChemComp-AJP: Digitonin / detergentYM / Digitonin ChemComp-OLA: OLEIC ACID / Oleic acid ChemComp-O50: 2-[(2P)-2',3-dimethyl[2,4'-bipyridin]-5-yl]-N-[(5P)-5-(pyrazin-2-yl)pyridin-2-yl]acetamide ChemComp-PAM: PALMITOLEIC ACID / Palmitoleic acid ChemComp-HEM: PROTOPORPHYRIN IX CONTAINING FE / Heme B ChemComp-PKZ*: Palmitoyl-CoA / Palmitoyl-CoA
Source	homo sapiens (human) mus musculus (house mouse)
Keywords	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