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- PDB-8j9n: Gq bound FZD1 in ligand-free state -

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Basic information

Entry
Database: PDB / ID: 8j9n
TitleGq bound FZD1 in ligand-free state
Components
  • Frizzled-1
  • Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
  • nanobody Nb35
KeywordsMEMBRANE PROTEIN / FZD1-Gq / class-F / Frizzled receptor / Complex
Function / homology
Function and homology information


muscular septum morphogenesis / regulation of mesenchymal stem cell differentiation / autocrine signaling / astrocyte-dopaminergic neuron signaling / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / presynapse assembly / Acetylcholine regulates insulin secretion / Wnt receptor activity / sensory perception of itch / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway ...muscular septum morphogenesis / regulation of mesenchymal stem cell differentiation / autocrine signaling / astrocyte-dopaminergic neuron signaling / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / presynapse assembly / Acetylcholine regulates insulin secretion / Wnt receptor activity / sensory perception of itch / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / membranous septum morphogenesis / non-canonical Wnt signaling pathway / endothelial cell differentiation / Wnt-protein binding / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / regulation of platelet activation / entrainment of circadian clock / midbrain dopaminergic neuron differentiation / hard palate development / frizzled binding / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / PCP/CE pathway / Class B/2 (Secretin family receptors) / Wnt signalosome / Disassembly of the destruction complex and recruitment of AXIN to the membrane / regulation of canonical Wnt signaling pathway / glutamate receptor signaling pathway / mast cell degranulation / outflow tract morphogenesis / adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway / adenylate cyclase-activating serotonin receptor signaling pathway / regulation of skeletal muscle contraction / phototransduction, visible light / PKA activation in glucagon signalling / negative regulation of BMP signaling pathway / hair follicle placode formation / developmental growth / intracellular transport / photoreceptor outer segment / positive regulation of osteoblast differentiation / canonical Wnt signaling pathway / regulation of presynapse assembly / D1 dopamine receptor binding / postsynaptic cytosol / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state / activation of adenylate cyclase activity / cellular response to acidic pH / adenylate cyclase-activating adrenergic receptor signaling pathway / hormone-mediated signaling pathway / cellular response to glucagon stimulus / intracellular glucose homeostasis / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / positive regulation of insulin secretion involved in cellular response to glucose stimulus / adenylate cyclase activator activity / trans-Golgi network membrane / GTPase activator activity / TCF dependent signaling in response to WNT / PDZ domain binding / Asymmetric localization of PCP proteins / neuropeptide signaling pathway / negative regulation of inflammatory response to antigenic stimulus / response to prostaglandin E / negative regulation of canonical Wnt signaling pathway / positive regulation of neuron projection development / bone development / G protein-coupled receptor binding / platelet aggregation / G protein-coupled receptor activity / cognition / G-protein beta/gamma-subunit complex binding / neuron differentiation / blood coagulation / Olfactory Signaling Pathway / Activation of the phototransduction cascade / positive regulation of insulin secretion / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / sensory perception of smell / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus
Similarity search - Function
G-protein alpha subunit, group Q / 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. ...G-protein alpha subunit, group Q / 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. / G-protein alpha subunit, group S / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Frizzled-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Vicugna pacos (alpaca)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLin, X. / Xu, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Discov / Year: 2024
Title: A framework for Frizzled-G protein coupling and implications to the PCP signaling pathways.
Authors: Zhibin Zhang / Xi Lin / Ling Wei / Yiran Wu / Lu Xu / Lijie Wu / Xiaohu Wei / Suwen Zhao / Xiangjia Zhu / Fei Xu /
Abstract: The ten Frizzled receptors (FZDs) are essential in Wnt signaling and play important roles in embryonic development and tumorigenesis. Among these, FZD6 is closely associated with lens development. ...The ten Frizzled receptors (FZDs) are essential in Wnt signaling and play important roles in embryonic development and tumorigenesis. Among these, FZD6 is closely associated with lens development. Understanding FZD activation mechanism is key to unlock these emerging targets. Here we present the cryo-EM structures of FZD6 and FZD3 which are known to relay non-canonical planar cell polarity (PCP) signaling pathways as well as FZD1 in their G protein-coupled states and in the apo inactive states, respectively. Comparison of the three inactive/active pairs unveiled a shared activation framework among all ten FZDs. Mutagenesis along with imaging and functional analysis on the human lens epithelial tissues suggested potential crosstalk between the G-protein coupling of FZD6 and the PCP signaling pathways. Together, this study provides an integrated understanding of FZD structure and function, and lays the foundation for developing therapeutic modulators to activate or inhibit FZD signaling for a range of disorders including cancers and cataracts.
History
DepositionMay 4, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release
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Revision 1.1Oct 16, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Frizzled-1
C: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
D: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: nanobody Nb35


Theoretical massNumber of molelcules
Total (without water)154,1525
Polymers154,1525
Non-polymers00
Water00
1


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

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Components

#1: Protein Frizzled-1 / Fz-1 / hFz1 / FzE1


Mass: 64015.668 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FZD1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UP38
#2: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha / Adenylate cyclase-stimulating G alpha protein / Guanine nucleotide-binding protein alpha-q


Mass: 28820.500 Da / Num. of mol.: 1 / Mutation: G49D,E50N,A249D,S252D,I372A,V375I
Source method: isolated from a genetically manipulated source
Details: Chimeric protein MiniGQ / Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP, GNAQ, GAQ / Production host: Escherichia coli (E. coli) / References: UniProt: P63092, UniProt: P50148
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7845.078 Da / Num. of mol.: 1 / Mutation: C68S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768
#5: Antibody nanobody Nb35


Mass: 16054.232 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vicugna pacos (alpaca) / Production host: Escherichia coli (E. coli)
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: FZD1-Gq complex in the ligand-free state / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Vicugna pacos (alpaca)30538
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Spodoptera frugiperda (fall armyworm)7108
21Escherichia coli (E. coli)562
31Trichoplusia ni (cabbage looper)7111
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: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 544329 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048994
ELECTRON MICROSCOPYf_angle_d0.80812185
ELECTRON MICROSCOPYf_dihedral_angle_d4.8011218
ELECTRON MICROSCOPYf_chiral_restr0.0471346
ELECTRON MICROSCOPYf_plane_restr0.0061554

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