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- EMDB-70662: Apo Human PORCN -

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Basic information

Entry
Database: EMDB / ID: EMD-70662
TitleApo Human PORCN
Map dataLocal resolution-filtered map from the final local refinement
Sample
  • Complex: Human Porcupine with inhibitor C59
    • Protein or peptide: Isoform 3 of Protein-serine O-palmitoleoyltransferase porcupine,Green fluorescent protein
  • Ligand: ZINC ION
Keywordstransmembrane protein / MBOAT / acylase / Wnt acylase / enzyme / ER / MEMBRANE PROTEIN
Function / homology
Function and homology information


[Wnt protein] O-palmitoleoyl transferase / protein palmitoleylation / palmitoleoyltransferase activity / LGK974 inhibits PORCN / protein lipidation / Wnt protein secretion / lipid modification / glycoprotein metabolic process / WNT ligand biogenesis and trafficking / Wnt-protein binding ...[Wnt protein] O-palmitoleoyl transferase / protein palmitoleylation / palmitoleoyltransferase activity / LGK974 inhibits PORCN / protein lipidation / Wnt protein secretion / lipid modification / glycoprotein metabolic process / WNT ligand biogenesis and trafficking / Wnt-protein binding / AMPA glutamate receptor complex / regulation of postsynaptic membrane neurotransmitter receptor levels / bioluminescence / generation of precursor metabolites and energy / Wnt signaling pathway / endoplasmic reticulum membrane / glutamatergic synapse / endoplasmic reticulum / membrane
Similarity search - Function
: / Membrane bound O-acyl transferase, MBOAT / MBOAT, membrane-bound O-acyltransferase family / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein
Similarity search - Domain/homology
Green fluorescent protein / Protein-serine O-palmitoleoyltransferase porcupine
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsBlack KA / Venugopal H / Glukhova A
Funding support Australia, 1 items
OrganizationGrant numberCountry
Other private Australia
CitationJournal: Commun Chem / Year: 2025
Title: Structural basis for Porcupine inhibition.
Authors: Katrina A Black / Jesse I Mobbs / Hariprasad Venugopal / Toby A Dite / Andrew Leis / Lilian Ll Wong / Laura F Dagley / David M Thal / Alisa Glukhova /
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)- ...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.
History
DepositionMay 15, 2025-
Header (metadata) releaseDec 10, 2025-
Map releaseDec 10, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70662.png

Downloads & links

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Map

FileDownload / File: emd_70662.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal resolution-filtered map from the final local refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 288 pix.
= 236.16 Å		0.82 Å/pix.
x 288 pix.
= 236.16 Å		0.82 Å/pix.
x 288 pix.
= 236.16 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.21788923 - 0.33733445
Average (Standard dev.)0.00022374539 (±0.0053028334)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 236.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_70662_msk_1.map
Projections & Slices
AxesZYX

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Histogram

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Additional map: Unsharpened map from the final local refinement

Fileemd_70662_additional_1.map
AnnotationUnsharpened map from the final local refinement
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Halfmap B from the final local refinement

Fileemd_70662_half_map_1.map
AnnotationHalfmap B from the final local refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Halfmap A from the final local refinement

Fileemd_70662_half_map_2.map
AnnotationHalfmap A from the final local refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

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Sample components

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Entire : Human Porcupine with inhibitor C59

EntireName: Human Porcupine with inhibitor C59
Components
  • Complex: Human Porcupine with inhibitor C59
    • Protein or peptide: Isoform 3 of Protein-serine O-palmitoleoyltransferase porcupine,Green fluorescent protein
  • Ligand: ZINC ION

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Supramolecule #1: Human Porcupine with inhibitor C59

SupramoleculeName: Human Porcupine with inhibitor C59 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 81 KDa

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Macromolecule #1: Isoform 3 of Protein-serine O-palmitoleoyltransferase porcupine,G...

MacromoleculeName: Isoform 3 of Protein-serine O-palmitoleoyltransferase porcupine,Green fluorescent protein
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: [Wnt protein] O-palmitoleoyl transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 81.758344 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATFSRQEFF QQLLQGCLLP TAQQGLDQIW LLLAICLACR LLWRLGLPSY LKHASTVAGG FFSLYHFFQL HMVWVVLLSL LCYLVLFLC RHSSHRGVFL SVTILIYLLM GEMHMVDTVT WHKMRGAQMI VAMKAVSLGF DLDRGEVGTV PSPVEFMGYL Y FVGTIVFG ...String:
MATFSRQEFF QQLLQGCLLP TAQQGLDQIW LLLAICLACR LLWRLGLPSY LKHASTVAGG FFSLYHFFQL HMVWVVLLSL LCYLVLFLC RHSSHRGVFL SVTILIYLLM GEMHMVDTVT WHKMRGAQMI VAMKAVSLGF DLDRGEVGTV PSPVEFMGYL Y FVGTIVFG PWISFHSYLQ AVQGRPLSAR WLQKVARSLA LALLCLVLST CVGPYLFPYF IPLNGDRLLR KGTMVRWLRA YE SAVSFHF SNYFVGFLSE ATATLAGAGF TEEKDHLEWD LTVSKPLNVE LPRSMVEVVT SWNLPMSYWL NNYVFKNALR LGT FSAVLV TYAASALLHG FSFHLAAVLL SLAFITYVEH VLRKRLARIL SACVLSKRCP PDCSHQHRLG LGVRALNLLF GALA IFHLA YLGSLFDVDV DDTTEEQGYG MAYTVHKWSE LSWASHWVTF GCWIFYRLIG AAAFESRLEV LFQGPAAAAV SKGEE LFTG VVPILVELDG DVNGHKFSVS GEGEGDATYG KLTLKFICTT GKLPVPWPTL VTTLTYGVQC FSRYPDHMKQ HDFFKS AMP EGYVQERTIF FKDDGNYKTR AEVKFEGDTL VNRIELKGID FKEDGNILGH KLEYNYNSHN VYIMADKQKN GIKVNFK IR HNIEDGSVQL ADHYQQNTPI GDGPVLLPDN HYLSTQSKLS KDPNEKRDHM VLLEFVTAAG ITLGMDELYK SGGSGWSH P QFEK

UniProtKB: Protein-serine O-palmitoleoyltransferase porcupine, Green fluorescent protein

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 31088
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: FLEXIBLE FIT
Output model

PDB-9oo8:
Apo Human PORCN

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