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Open data
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Basic information
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Title | Human PORCN in complex with palmitoleoylated WNT3A peptide![]() | |||||||||
![]() | membrane protein![]() | |||||||||
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Function / homology | ![]() [Wnt protein] O-palmitoleoyl transferase / Wnt signaling pathway involved in forebrain neuroblast division / positive regulation of dermatome development / axis elongation involved in somitogenesis / calcium ion transmembrane transport via low voltage-gated calcium channel / : / LGK974 inhibits PORCN / protein palmitoleylation / positive regulation of collateral sprouting in absence of injury / palmitoleoyltransferase activity ...[Wnt protein] O-palmitoleoyl transferase / Wnt signaling pathway involved in forebrain neuroblast division / positive regulation of dermatome development / axis elongation involved in somitogenesis / calcium ion transmembrane transport via low voltage-gated calcium channel / : / LGK974 inhibits PORCN / protein palmitoleylation / positive regulation of collateral sprouting in absence of injury / palmitoleoyltransferase activity / positive regulation of mesodermal cell fate specification / paraxial mesodermal cell fate commitment / Specification of the neural plate border / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
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Method | ![]() ![]() | |||||||||
![]() | Liu Y / Qi X / Li X | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Mechanisms and inhibition of Porcupine-mediated Wnt acylation. Authors: Yang Liu / Xiaofeng Qi / Linda Donnelly / Nadia Elghobashi-Meinhardt / Tao Long / Rich W Zhou / Yingyuan Sun / Boyuan Wang / Xiaochun Li / ![]() ![]() 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. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
Map data | ![]() | 43.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 19.9 KB 19.9 KB | Display Display | ![]() |
Images | ![]() | 49.3 KB | ||
Others | ![]() ![]() | 77.6 MB 77.6 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7ureMC ![]() 7uraC ![]() 7urcC ![]() 7urdC ![]() 7urfC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | membrane protein | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.83 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: membrane protein
File | emd_26710_half_map_1.map | ||||||||||||
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Annotation | membrane protein | ||||||||||||
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Density Histograms |
-Half map: membrane protein
File | emd_26710_half_map_2.map | ||||||||||||
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Annotation | membrane protein | ||||||||||||
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Density Histograms |
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Sample components
+Entire : product-bound human PORCN
+Supramolecule #1: product-bound human PORCN
+Supramolecule #2: Isoform 2 of Protein-serine O-palmitoleoyltransferase porcupine (...
+Supramolecule #3: 2C11 light chain, 2C11 heavy chain
+Supramolecule #4: Isoform 2 of Protein Wnt-3a
+Macromolecule #1: Isoform 2 of Protein-serine O-palmitoleoyltransferase porcupine
+Macromolecule #2: 2C11 light chain
+Macromolecule #3: 2C11 heavy chain
+Macromolecule #4: Isoform 2 of Protein Wnt-3a
+Macromolecule #5: Digitonin
+Macromolecule #6: ZINC ION
+Macromolecule #7: PALMITOLEIC ACID
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 8.5 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Initial angle assignment | Type: NOT APPLICABLE |
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Final angle assignment | Type: NOT APPLICABLE |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 113566 |