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- EMDB-38769: Structure of Platelet-activating factor receptor-G protein comple... -

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Entry
Database: EMDB / ID: EMD-38769
TitleStructure of Platelet-activating factor receptor-G protein complex bound to platelet-activating factor
Map data
Sample
  • Complex: PTAFR-PAF G protein complex
    • Protein or peptide: Platelet-activating factor receptor
    • 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: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: scFv16
  • Ligand: (2R)-2-(acetyloxy)-3-(hexadecyloxy)propyl 2-(trimethylammonio)ethyl phosphate
KeywordsGPCR / PTAFR / MEMBRANE PROTEIN
Function / homology
Function and homology information


cellular response to gravity / positive regulation of maternal process involved in parturition / positive regulation of gastro-intestinal system smooth muscle contraction / cellular response to 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine / positive regulation of transcytosis / platelet activating factor receptor activity / positive regulation of cellular extravasation / inositol trisphosphate biosynthetic process / response to symbiotic bacterium / G protein-coupled purinergic nucleotide receptor activity ...cellular response to gravity / positive regulation of maternal process involved in parturition / positive regulation of gastro-intestinal system smooth muscle contraction / cellular response to 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine / positive regulation of transcytosis / platelet activating factor receptor activity / positive regulation of cellular extravasation / inositol trisphosphate biosynthetic process / response to symbiotic bacterium / G protein-coupled purinergic nucleotide receptor activity / positive regulation of neutrophil degranulation / lipopolysaccharide immune receptor activity / parturition / positive regulation of leukocyte tethering or rolling / transcytosis / Class A/1 (Rhodopsin-like receptors) / mitogen-activated protein kinase binding / cellular response to fatty acid / positive regulation of inositol phosphate biosynthetic process / Interleukin-10 signaling / response to dexamethasone / tertiary granule membrane / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / negative regulation of blood pressure / cellular response to cAMP / cellular response to forskolin / regulation of mitotic spindle organization / secretory granule membrane / positive regulation of translation / Regulation of insulin secretion / positive regulation of smooth muscle cell proliferation / lipopolysaccharide binding / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / phospholipid binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / positive regulation of interleukin-6 production / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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 / G protein-coupled acetylcholine 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 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Interferon gamma signaling / Sensory perception of sweet, bitter, and umami (glutamate) taste / chemotaxis / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / positive regulation of tumor necrosis factor production / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / 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 / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events
Similarity search - Function
Platelet-activating factor receptor / G-protein alpha subunit, group I / 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 ...Platelet-activating factor receptor / G-protein alpha subunit, group I / 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 coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / 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
Platelet-activating factor receptor / 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(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsFan W / Xu Y / Zhuang Y / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81902085 China
CitationJournal: Cell Rep / Year: 2024
Title: Molecular basis for the activation of PAF receptor by PAF.
Authors: Wenjia Fan / Youwei Xu / Xinheng He / Ping Luo / Jingpeng Zhu / Junrui Li / Ruolan Wang / Qingning Yuan / Kai Wu / Wen Hu / Yuxi Zhao / Shiqi Xu / Xi Cheng / Yue Wang / H Eric Xu / Youwen Zhuang /
Abstract: Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug ...Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug development targeting the PAFR has been limited, partly due to an incomplete understanding of its activation mechanism. Here, we present a 2.9-Å structure of the PAF-bound PAFR-G complex. Structural and mutagenesis analyses unveil a specific binding mode of PAF, with the choline head forming cation-π interactions within PAFR hydrophobic pocket, while the alkyl tail penetrates deeply into an aromatic cleft between TM4 and TM5. Binding of PAF modulates conformational changes in key motifs of PAFR, triggering the outward movement of TM6, TM7, and helix 8 for G protein coupling. Molecular dynamics simulation suggests a membrane-side pathway for PAF entry into PAFR via the TM4-TM5 cavity. By providing molecular insights into PAFR signaling, this work contributes a foundation for developing therapeutic interventions targeting PAF signal axis.
History
DepositionJan 19, 2024-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateNov 27, 2024-
Current statusNov 27, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_38769.png

Downloads & links

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Map

FileDownload / File: emd_38769.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 300 pix.
= 247.2 Å		0.82 Å/pix.
x 300 pix.
= 247.2 Å		0.82 Å/pix.
x 300 pix.
= 247.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.011131955 - 0.039213233
Average (Standard dev.)0.00003239108 (±0.0017321431)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 247.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_38769_additional_1.map
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Half map: #1

Fileemd_38769_half_map_1.map
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Half map: #2

Fileemd_38769_half_map_2.map
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Sample components

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Entire : PTAFR-PAF G protein complex

EntireName: PTAFR-PAF G protein complex
Components
  • Complex: PTAFR-PAF G protein complex
    • Protein or peptide: Platelet-activating factor receptor
    • 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: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: scFv16
  • Ligand: (2R)-2-(acetyloxy)-3-(hexadecyloxy)propyl 2-(trimethylammonio)ethyl phosphate

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Supramolecule #1: PTAFR-PAF G protein complex

SupramoleculeName: PTAFR-PAF G protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Platelet-activating factor receptor

MacromoleculeName: Platelet-activating factor receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.24227 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MEPHDSSHMD SEFRYTLFPI VYSIIFVLGV IANGYVLWVF ARLYPCKKFN EIKIFMVNLT MADMLFLITL PLWIVYYQNQ GNWILPKFL CNVAGCLFFI NTYCSVAFLG VITYNRFQAV TRPIKTAQAN TRKRGISLSL VIWVAIVGAA SYFLILDSTN T VPDSAGSG ...String:
MEPHDSSHMD SEFRYTLFPI VYSIIFVLGV IANGYVLWVF ARLYPCKKFN EIKIFMVNLT MADMLFLITL PLWIVYYQNQ GNWILPKFL CNVAGCLFFI NTYCSVAFLG VITYNRFQAV TRPIKTAQAN TRKRGISLSL VIWVAIVGAA SYFLILDSTN T VPDSAGSG NVTRCFEHYE KGSVPVLIIH IFIVFSFFLV FLIILFCNLV IIRTLLMQPV QQQRNAEVKR RALWMVCTVL AV FIICFVP HHVVQLPWTL AELGFQDSKF HQAINDAHQV TLCLLSTNCV LDPVIYCFLT KKFRKHLTEK FYSMRSSRKC SRA TTDTVT EVVVPFNQIP GNSLKN

UniProtKB: Platelet-activating factor receptor

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Macromolecule #2: 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: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.784301 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GSLLQSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...String:
GSLLQSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWN

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

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.56375 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFC

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

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Macromolecule #4: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.313863 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GCTLSAEDKA AVERSKMIDR NLREDGEKAA REVKLLLLGA GESGKSTIVK QMKIIHEAGY SEEECKQYKA VVYSNTIQSI IAIIRAMGR LKIDFGDSAR ADDARQLFVL AGAAEEGFMT AELAGVIKRL WKDSGVQACF NRSREYQLND SAAYYLNDLD R IAQPNYIP ...String:
GCTLSAEDKA AVERSKMIDR NLREDGEKAA REVKLLLLGA GESGKSTIVK QMKIIHEAGY SEEECKQYKA VVYSNTIQSI IAIIRAMGR LKIDFGDSAR ADDARQLFVL AGAAEEGFMT AELAGVIKRL WKDSGVQACF NRSREYQLND SAAYYLNDLD R IAQPNYIP TQQDVLRTRV KTTGIVETHF TFKDLHFKMF DVGAQRSERK KWIHCFEGVT AIIFCVALSD YDLVLAEDEE MN RMHESMK LFDSICNNKW FTDTSIILFL NKKDLFEEKI KKSPLTICYP EYAGSNTYEE AAAYIQCQFE DLNKRKDTKE IYT HFTCST DTKNVQFVFD AVTDVIIKNN LKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.277299 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL

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Macromolecule #6: (2R)-2-(acetyloxy)-3-(hexadecyloxy)propyl 2-(trimethylammonio)eth...

MacromoleculeName: (2R)-2-(acetyloxy)-3-(hexadecyloxy)propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 6 / Number of copies: 1 / Formula: PFS
Molecular weightTheoretical: 523.683 Da
Chemical component information

ChemComp-PFS:
(2R)-2-(acetyloxy)-3-(hexadecyloxy)propyl 2-(trimethylammonio)ethyl phosphate

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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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: AlphaFold2 model
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 346106
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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