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- PDB-7ure: Human PORCN in complex with palmitoleoylated WNT3A peptide -

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Basic information

Entry
Database: PDB / ID: 7ure
TitleHuman PORCN in complex with palmitoleoylated WNT3A peptide
Components
  • 2C11 heavy chain
  • 2C11 light chain
  • Isoform 2 of Protein-serine O-palmitoleoyltransferase porcupine
  • Protein Wnt-3a
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / product-bound / complex / TRANSFERASE / TRANSFERASE-TRANSFERASE PRODUCT complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


[Wnt protein] O-palmitoleoyl transferase / protein lipidation / cell proliferation in midbrain / protein palmitoleylation / positive regulation of dermatome development / calcium ion transmembrane transport via low voltage-gated calcium channel / palmitoleoyltransferase activity / LGK974 inhibits PORCN / positive regulation of mesodermal cell fate specification / Formation of the posterior neural plate ...[Wnt protein] O-palmitoleoyl transferase / protein lipidation / cell proliferation in midbrain / protein palmitoleylation / positive regulation of dermatome development / calcium ion transmembrane transport via low voltage-gated calcium channel / palmitoleoyltransferase activity / LGK974 inhibits PORCN / positive regulation of mesodermal cell fate specification / Formation of the posterior neural plate / Wnt protein secretion / lipid modification / Wnt-Frizzled-LRP5/6 complex / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / Signaling by RNF43 mutants / COP9 signalosome assembly / WNT ligand biogenesis and trafficking / cell proliferation in forebrain / Specification of the neural plate border / positive regulation of skeletal muscle tissue development / secondary palate development / presynapse assembly / cardiac muscle cell fate commitment / synaptic vesicle recycling / co-receptor binding / non-canonical Wnt signaling pathway / negative regulation of dopaminergic neuron differentiation / Wnt-protein binding / regulation of postsynapse to nucleus signaling pathway / positive regulation of cardiac muscle cell differentiation / midbrain dopaminergic neuron differentiation / frizzled binding / Class B/2 (Secretin family receptors) / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Formation of paraxial mesoderm / cell fate commitment / regulation of synapse organization / canonical Wnt signaling pathway / AMPA glutamate receptor complex / positive regulation of receptor internalization / regulation of presynapse assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / cellular response to retinoic acid / Transcriptional and post-translational regulation of MITF-M expression and activity / Regulation of FZD by ubiquitination / cytokine activity / positive regulation of protein localization to plasma membrane / negative regulation of neuron projection development / TCF dependent signaling in response to WNT / Wnt signaling pathway / negative regulation of neurogenesis / Golgi lumen / modulation of chemical synaptic transmission / heart development / positive regulation of canonical Wnt signaling pathway / endocytic vesicle membrane / neuron differentiation / presynapse / early endosome membrane / transcription coactivator activity / endoplasmic reticulum lumen / receptor ligand activity / protein domain specific binding / signaling receptor binding / positive regulation of gene expression / positive regulation of DNA-templated transcription / endoplasmic reticulum membrane / glutamatergic synapse / cell surface / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / : / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane
Similarity search - Function
Wnt-3 protein / : / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain / wnt family / found in Wnt-1 / Membrane bound O-acyl transferase, MBOAT / MBOAT, membrane-bound O-acyltransferase family
Similarity search - Domain/homology
PALMITOLEIC ACID / Protein Wnt-3a / Protein-serine O-palmitoleoyltransferase porcupine
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.19 Å
AuthorsLiu, Y. / Qi, X. / Li, X.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
Welch Foundation United States
CitationJournal: Nature / Year: 2022
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.
History
DepositionApr 21, 2022Deposition site: RCSB / Processing site: RCSB
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Revision 1.1Aug 3, 2022Group: Database references / Category: citation / citation_author
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Revision 2.0Dec 25, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Polymer sequence / Structure summary
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 2 of Protein-serine O-palmitoleoyltransferase porcupine
L: 2C11 light chain
H: 2C11 heavy chain
B: Protein Wnt-3a
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,5097
Polymers107,9604
Non-polymers1,5493
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Antibody , 2 types, 2 molecules LH

#2: Antibody 2C11 light chain


Mass: 25673.693 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Antibody 2C11 heavy chain


Mass: 26933.135 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein Isoform 2 of Protein-serine O-palmitoleoyltransferase porcupine / Protein MG61


Mass: 52824.652 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PORCN, MG61, PORC, PPN / Production host: Homo sapiens (human)
References: UniProt: Q9H237, [Wnt protein] O-palmitoleoyl transferase
#4: Protein/peptide Protein Wnt-3a


Mass: 2528.051 Da / Num. of mol.: 1 / Fragment: residues 199-220 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P56704

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Non-polymers , 3 types, 3 molecules

#5: Chemical ChemComp-AJP / Digitonin


Mass: 1229.312 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C56H92O29 / Comment: detergent*YM
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#7: Chemical ChemComp-PAM / PALMITOLEIC ACID


Mass: 254.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H30O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1product-bound human PORCNCOMPLEX#1-#40RECOMBINANT
2Isoform 2 of Protein-serine O-palmitoleoyltransferase porcupine (E.C.2.3.1.250)COMPLEX#11RECOMBINANT
32C11 light chain, 2C11 heavy chainCOMPLEX#2-#31RECOMBINANT
4Isoform 2 of Protein Wnt-3aCOMPLEX#41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 8.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113566 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035646
ELECTRON MICROSCOPYf_angle_d0.5867681
ELECTRON MICROSCOPYf_dihedral_angle_d7.2323173
ELECTRON MICROSCOPYf_chiral_restr0.045867
ELECTRON MICROSCOPYf_plane_restr0.005921

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