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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 / hard palate development / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / Wnt receptor activity / non-canonical Wnt signaling pathway ...muscular septum morphogenesis / regulation of mesenchymal stem cell differentiation / autocrine signaling / astrocyte-dopaminergic neuron signaling / hard palate development / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / Wnt receptor activity / non-canonical Wnt signaling pathway / membranous septum morphogenesis / presynapse assembly / phospholipase C-activating serotonin receptor signaling pathway / PLC beta mediated events / Wnt-protein binding / midbrain dopaminergic neuron differentiation / endothelial cell differentiation / entrainment of circadian clock / regulation of platelet activation / 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 / outflow tract morphogenesis / phototransduction, visible light / postsynaptic cytosol / PKA activation in glucagon signalling / negative regulation of BMP signaling pathway / regulation of presynapse assembly / hair follicle placode formation / photoreceptor outer segment / developmental growth / neuropeptide signaling pathway / canonical Wnt signaling pathway / D1 dopamine receptor binding / intracellular transport / positive regulation of osteoblast differentiation / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / enzyme regulator activity / response to prostaglandin E / regulation of insulin secretion / cellular response to glucagon stimulus / GTPase activator activity / adenylate cyclase activator activity / positive regulation of DNA-binding transcription factor activity / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / trans-Golgi network membrane / negative regulation of protein kinase activity / TCF dependent signaling in response to WNT / PDZ domain binding / Asymmetric localization of PCP proteins / negative regulation of inflammatory response to antigenic stimulus / G protein-coupled receptor binding / negative regulation of canonical Wnt signaling pathway / G protein-coupled receptor activity / bone development / positive regulation of neuron projection development / G-protein beta/gamma-subunit complex binding / platelet aggregation / Olfactory Signaling Pathway / cognition / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / neuron differentiation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / blood coagulation / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / sensory perception of smell
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 / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / 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. / WD domain, G-beta repeat / 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
Revision 1.1Oct 16, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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

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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