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- EMDB-36111: Gq bound FZD1 in ligand-free state -

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Entry
Database: EMDB / ID: EMD-36111
TitleGq bound FZD1 in ligand-free state
Map data
Sample
  • Complex: FZD1-Gq complex in the ligand-free state
    • Protein or peptide: Frizzled-1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: nanobody Nb35
KeywordsFZD1-Gq / class-F / Frizzled receptor / Complex / MEMBRANE PROTEIN
Function / homology
Function and homology information


: / muscular septum morphogenesis / regulation of mesenchymal stem cell differentiation / autocrine signaling / planar cell polarity pathway involved in neural tube closure / astrocyte-dopaminergic neuron signaling / canonical Wnt signaling pathway involved in mesenchymal stem cell differentiation / hard palate development / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion ...: / muscular septum morphogenesis / regulation of mesenchymal stem cell differentiation / autocrine signaling / planar cell polarity pathway involved in neural tube closure / astrocyte-dopaminergic neuron signaling / canonical Wnt signaling pathway involved in mesenchymal stem cell differentiation / hard palate development / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / Wnt receptor activity / membranous septum morphogenesis / non-canonical Wnt signaling pathway / presynapse assembly / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / Wnt-protein binding / entrainment of circadian clock / regulation of platelet activation / midbrain dopaminergic neuron differentiation / endothelial cell differentiation / phototransduction, visible light / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / frizzled binding / glutamate receptor signaling pathway / PCP/CE pathway / Wnt signalosome / regulation of canonical Wnt signaling pathway / Class B/2 (Secretin family receptors) / Disassembly of the destruction complex and recruitment of AXIN to the membrane / action potential / outflow tract morphogenesis / PKA activation in glucagon signalling / activation of phospholipase C activity / regulation of presynapse assembly / hair follicle placode formation / intracellular transport / negative regulation of BMP signaling pathway / photoreceptor outer segment / D1 dopamine receptor binding / developmental growth / canonical Wnt signaling pathway / positive regulation of osteoblast differentiation / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / GTPase activator activity / trans-Golgi network membrane / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / G protein-coupled receptor binding / PDZ domain binding / G protein-coupled receptor activity / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / negative regulation of canonical Wnt signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of neuron projection development / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / neuron differentiation / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / Glucagon-type ligand receptors / cognition / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle
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-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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 / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLin X / Xu F
Funding support1 items
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, 2023-
Header (metadata) releaseJan 17, 2024-
Map releaseJan 17, 2024-
UpdateJan 17, 2024-
Current statusJan 17, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36111.png

Downloads & links

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Map

FileDownload / File: emd_36111.map.gz / Format: CCP4 / Size: 55.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.0017412013 - 2.021513
Average (Standard dev.)0.0011545139 (±0.024303826)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions244244244
Spacing244244244
CellA=B=C: 258.63998 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_36111_additional_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36111_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36111_half_map_2.map
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Sample components

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Entire : FZD1-Gq complex in the ligand-free state

EntireName: FZD1-Gq complex in the ligand-free state
Components
  • Complex: FZD1-Gq complex in the ligand-free state
    • Protein or peptide: Frizzled-1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: nanobody Nb35

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Supramolecule #1: FZD1-Gq complex in the ligand-free state

SupramoleculeName: FZD1-Gq complex in the ligand-free state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Frizzled-1

MacromoleculeName: Frizzled-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.015668 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GVRAQAAGQG PGQGPGPGQQ PPPPPQQQQS GQQYNGERGI SVPDHGYCQP ISIPLCTDIA YNQTIMPNLL GHTNQEDAGL EVHQFYPLV KVQCSAELKF FLCSMYAPVC TVLEQALPPC RSLCERARQG CEALMNKFGF QWPDTLKCEK FPVHGAGELC V GQNTSDKG ...String:
GVRAQAAGQG PGQGPGPGQQ PPPPPQQQQS GQQYNGERGI SVPDHGYCQP ISIPLCTDIA YNQTIMPNLL GHTNQEDAGL EVHQFYPLV KVQCSAELKF FLCSMYAPVC TVLEQALPPC RSLCERARQG CEALMNKFGF QWPDTLKCEK FPVHGAGELC V GQNTSDKG TPTPSLLPEF WTSNPQHGGG GHRGGFPGGA GASERGKFSC PRALKVPSYL NYHFLGEKDC GAPCEPTKVY GL MYFGPEE LRFSRTWIGI WSVLCCASTL FTVLTYLVDM RRFSYPERPI IFLSGCYTAV AVAYIAGFLL EDRVVCNDKF AED GARTVA QGTKKEGCTI LFMMLYFFSM ASSIWWVILS LTWFLAAGMK WGHEAIEANS QYFHLAAWAV PAIKTITILA LGQV DGDVL SGVCFVGLNN VDALRGFVLA PLFVYLFIGT SFLLAGFVSL FRIRTIMKHD GTKTEKLEKL MVRIGVFSVL YTVPA TIVI ACYFYEQAFR DQWERSWVAQ SCKSYAIPCP HLQAGGGAPP HPPMSPDFTV FMIKYLMTLI VGITSGFWIW SGKTLN SWR KFYTRLTNSK QGETTV

UniProtKB: Frizzled-1

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Macromolecule #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms sh...

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
type: protein_or_peptide / ID: 2 / Details: Chimeric protein MiniGQ / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.8205 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GNSKTEDQRN EEKAQREANK KIEQLRRDKR DARRATHRLL LLGADNSGKS TIVKQMRILH GGSGGSGGTS GIFETKFQVD KVNFHMFDV GGQRDERRKW IQCFNDVTAI IFVVDSSDYN RLQEALNLFK SIWNNRWLRT ISVILFLNKQ DLLAEKVLAG K SKIEDYFP ...String:
GNSKTEDQRN EEKAQREANK KIEQLRRDKR DARRATHRLL LLGADNSGKS TIVKQMRILH GGSGGSGGTS GIFETKFQVD KVNFHMFDV GGQRDERRKW IQCFNDVTAI IFVVDSSDYN RLQEALNLFK SIWNNRWLRT ISVILFLNKQ DLLAEKVLAG K SKIEDYFP EFARYTTPED ATPEPGEDPR VTRAKYFIRD EFLRISTASG DGRHYCYPHF TCAVDTENAR RIFNDCKDTI LQ LNLKEYN LV

UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(s) subunit alpha isoforms ...UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(q) subunit alpha

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.41693 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.845078 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFSAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #5: nanobody Nb35

MacromoleculeName: nanobody Nb35 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 16.054232 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MKYLLPTAAA GLLLLAAQPA MAMQVQLQES GGGLVQPGGS LRLSCAASGF TFSNYKMNWV RQAPGKGLEW VSDISQSGAS ISYTGSVKG RFTISRDNAK NTLYLQMNSL KPEDTAVYYC ARCPAPFTRD CFDVTSTTYA YRGQGTQVTV

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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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 544329
FSC plot (resolution estimation)

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