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- PDB-9rhg: FZD7 in complex with negative allosteric modulator C407 -

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Basic information

Entry
Database: PDB / ID: 9rhg
TitleFZD7 in complex with negative allosteric modulator C407
ComponentsFrizzled-7
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor / Frizzled / negative allosteric modulator / small molecule
Function / homology
Function and homology information


negative regulation of ectodermal cell fate specification / negative regulation of cardiac muscle cell differentiation / somatic stem cell division / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / non-canonical Wnt signaling pathway / Wnt receptor activity / mesenchymal to epithelial transition / positive regulation of epithelial cell proliferation involved in wound healing / Wnt-protein binding / WNT5:FZD7-mediated leishmania damping ...negative regulation of ectodermal cell fate specification / negative regulation of cardiac muscle cell differentiation / somatic stem cell division / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / non-canonical Wnt signaling pathway / Wnt receptor activity / mesenchymal to epithelial transition / positive regulation of epithelial cell proliferation involved in wound healing / Wnt-protein binding / WNT5:FZD7-mediated leishmania damping / frizzled binding / PCP/CE pathway / Class B/2 (Secretin family receptors) / regulation of canonical Wnt signaling pathway / Wnt signaling pathway, planar cell polarity pathway / stem cell population maintenance / positive regulation of phosphorylation / negative regulation of cell-substrate adhesion / canonical Wnt signaling pathway / cellular response to retinoic acid / phosphatidylinositol-4,5-bisphosphate binding / substrate adhesion-dependent cell spreading / PDZ domain binding / Asymmetric localization of PCP proteins / positive regulation of JNK cascade / G protein-coupled receptor activity / recycling endosome membrane / neuron differentiation / T cell differentiation in thymus / positive regulation of MAPK cascade / intracellular membrane-bounded organelle / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / membrane / plasma membrane
Similarity search - Function
Frizzled-7, cysteine-rich Wnt-binding domain / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain / Frizzled (fz) domain profile. ...Frizzled-7, cysteine-rich Wnt-binding domain / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain / Frizzled (fz) domain profile. / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2.
Similarity search - Domain/homology
: / CHOLESTEROL HEMISUCCINATE / Frizzled-7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsScharf, M.M. / Graetz, L. / Kinsolving, J. / Voss, J. / Carrasco-Busturia, D. / Forsberg, B. / Kolb, P. / Schulte, G.
Funding support Sweden, Denmark, Germany, European Union, 14items
OrganizationGrant numberCountry
Swedish Research Council2017-04676 Sweden
Swedish Research Council2019-01190 Sweden
Swedish Research Council2024-02515 Sweden
CancerfondenCAN2017/561 Sweden
Cancerfonden20 1102 PjF Sweden
Cancerfonden23 2825 Pj Sweden
Novo Nordisk FoundationNNF21OC0070008 Denmark
Novo Nordisk FoundationNNF22OC0078104 Denmark
German Research Foundation (DFG)504098926 Germany
German Research Foundation (DFG)470002134 Germany
German Research Foundation (DFG)520506488 Germany
Knut and Alice Wallenberg FoundationKAW 2020.0239 Sweden
European Union (EU)101199012European Union
Swedish Research Council2022-06725 Sweden
CitationJournal: Nat Commun / Year: 2025
Title: In silico docking yields small molecule negative allosteric modulators targeting the core of Frizzled 7.
Authors: Magdalena M Scharf / Julia Kinsolving / Lukas Grätz / Jan Hendrik Voss / David Carrasco-Busturia / Björn Forsberg / Peter Kolb / Gunnar Schulte /
Abstract: Targeting the Frizzled family (FZD) of WNT receptors pharmacologically has, despite substantial therapeutic potential, proven difficult. Given an almost complete lack of validated, effective small ...Targeting the Frizzled family (FZD) of WNT receptors pharmacologically has, despite substantial therapeutic potential, proven difficult. Given an almost complete lack of validated, effective small molecules targeting FZDs, no putative ligand binding site has so far been identified. In order to target FZD, a potential target for the treatment of intestinal tumors, we combine an approach of adapted docking setups and large molecular library docking screens, identifying compound C407. Applying pharmacological assays, genetically-encoded biosensors, site-directed mutagenesis, cryo-electron microscopy and molecular dynamics simulations, the compound binding site in the core of the seven transmembrane bundle is validated and C407 is confirmed as a negative allosteric modulator of WNT-induced and FZD-mediated WNT/β-catenin signaling. In summary, we provide here the proof-of-principle that targeting FZDs with small molecule compounds is possible and effective. Future hit optimization and functional validation in disease-relevant in vitro and in vivo models will pave the way towards clinical exploration.
History
DepositionJun 9, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 24, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Frizzled-7
A: Frizzled-7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,2587
Polymers134,9222
Non-polymers2,3365
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Frizzled-7 / Fz-7 / hFz7 / FzE3


Mass: 67460.859 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Expression tag position 1-24, expression tag 578-605
Source: (gene. exp.) Homo sapiens (human) / Gene: FZD7 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O75084
#2: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H50O4
#3: Chemical ChemComp-A1JGQ / ethyl 3-[2-[(2-fluorophenyl)amino]-2-oxidanylidene-ethyl]-5-methyl-4-oxidanylidene-thieno[2,3-d]pyrimidine-6-carboxylate


Mass: 389.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16FN3O4S / Feature type: SUBJECT OF INVESTIGATION
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

ComponentName: FZD7 in complex with the negative allosteric modulator C407
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMTRISTRIS1
2100 mMsodium chlorideNaCl1
30.002 %lauryl maltose neopentyl glycolLMNG1
40.0002 %cholesterol hemisuccinateCHS1
50.0002 %glyco-diosgeninGDN1
SpecimenConc.: 2.88 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Purified protein sample was supplemented with a 10:1 molar ratio of C407 (prepared in DMSO) to FZD7 prior to grid freezing.
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 400 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 1.4 sec. / Electron dose: 80.1 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 19899
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1Topaz0.2.5particle selection
2cryoSPARC4.07image acquisition
4cryoSPARCv4.7.0CTF correction
7Coot0.9.8.95model fitting
9PHENIX1.21_5207model refinement
10cryoSPARCv4.7.0initial Euler assignment
11cryoSPARCv4.7.0final Euler assignment
12cryoSPARCv4.7.0classification
13cryoSPARCv4.7.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionDetails: Blob picker
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 191045 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Atomic model buildingPDB-ID: 9EPO

9epo


Accession code: 9EPO / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.5 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035967
ELECTRON MICROSCOPYf_angle_d0.6658135
ELECTRON MICROSCOPYf_dihedral_angle_d14.2662294
ELECTRON MICROSCOPYf_chiral_restr0.04880
ELECTRON MICROSCOPYf_plane_restr0.006976

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