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- PDB-7t6b: Structure of S1PR2-heterotrimeric G13 signaling complex -

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Basic information

Entry
Database: PDB / ID: 7t6b
TitleStructure of S1PR2-heterotrimeric G13 signaling complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Sphingosine 1-phosphate receptor 2
  • scFv16
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / S1P / S1PR2 / GPCR / membrane protein / cryo-EM / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


D5 dopamine receptor binding / positive regulation of establishment of endothelial barrier / regulation of fibroblast migration / sphingosine-1-phosphate receptor activity / Lysosphingolipid and LPA receptors / negative regulation of vascular associated smooth muscle cell migration / negative regulation of excitatory postsynaptic potential / filopodium assembly / G protein-coupled peptide receptor activity / regulation of metabolic process ...D5 dopamine receptor binding / positive regulation of establishment of endothelial barrier / regulation of fibroblast migration / sphingosine-1-phosphate receptor activity / Lysosphingolipid and LPA receptors / negative regulation of vascular associated smooth muscle cell migration / negative regulation of excitatory postsynaptic potential / filopodium assembly / G protein-coupled peptide receptor activity / regulation of metabolic process / sphingosine-1-phosphate receptor signaling pathway / regulation of small GTPase mediated signal transduction / NRAGE signals death through JNK / branching involved in blood vessel morphogenesis / negative regulation of vascular associated smooth muscle cell proliferation / Rho protein signal transduction / CDC42 GTPase cycle / RAC1 GTPase cycle / excitatory postsynaptic potential / guanyl-nucleotide exchange factor activity / positive regulation of peptidyl-threonine phosphorylation / G protein-coupled receptor binding / G protein-coupled receptor activity / brush border membrane / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / platelet activation / G protein activity / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / regulation of blood pressure / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / integrin binding / melanosome / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / regulation of cell shape / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / actin cytoskeleton organization / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / in utero embryonic development / Ras protein signal transduction / postsynapse / cell population proliferation / Extra-nuclear estrogen signaling / cell differentiation / G protein-coupled receptor signaling pathway / lysosomal membrane / focal adhesion / GTPase activity / lipid binding / positive regulation of cell population proliferation / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / nucleus
Similarity search - Function
EDG-5 sphingosine 1-phosphate receptor / G-protein alpha subunit, group 12/13 / Sphingosine 1-phosphate receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 ...EDG-5 sphingosine 1-phosphate receptor / G-protein alpha subunit, group 12/13 / Sphingosine 1-phosphate receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / 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
Chem-S1P / Sphingosine 1-phosphate receptor 2 / 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 subunit alpha-13
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.19 Å
AuthorsLi, X. / Chen, H.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01HL020948 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM135343 United States
Damon Runyon Cancer Research FoundationDRR-53S-19 United States
CitationJournal: Sci Adv / Year: 2022
Title: Structure of S1PR2-heterotrimeric G signaling complex.
Authors: Hongwen Chen / Kevin Chen / Weijiao Huang / Louis M Staudt / Jason G Cyster / Xiaochun Li /
Abstract: Sphingosine-1-phosphate (S1P) regulates immune cell trafficking, angiogenesis, and vascular function via its five receptors. Inherited mutations in S1P receptor 2 (S1PR2) occur in individuals with ...Sphingosine-1-phosphate (S1P) regulates immune cell trafficking, angiogenesis, and vascular function via its five receptors. Inherited mutations in S1P receptor 2 (S1PR2) occur in individuals with hearing loss, and acquired mutations in S1PR2 and G occur in a malignant lymphoma. Here, we present the cryo-electron microscopy structure of S1P-bound S1PR2 coupled to the heterotrimeric G. Interaction between S1PR2 intracellular loop 2 (ICL2) and transmembrane helix 4 confines ICL2 to engage the α5 helix of G. Transforming growth factor-α shedding assays and cell migration assays support the key roles of the residues in S1PR2-G complex assembly. The structure illuminates the mechanism of receptor disruption by disease-associated mutations. Unexpectedly, we showed that FTY720-P, an agonist of the other four S1PRs, can trigger G activation via S1PR2. S1PR2 variant can increase the activity of G considerably with FTY720-P and S1P, thus revealing a basis for S1PR drug selectivity.
History
DepositionDec 13, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein subunit alpha-13
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: scFv16
R: Sphingosine 1-phosphate receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,1546
Polymers157,7755
Non-polymers3791
Water00
1


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

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ACD

#1: Protein Guanine nucleotide-binding protein subunit alpha-13 / G alpha-13 / G-protein subunit alpha-13


Mass: 42255.273 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNA13 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14344
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39970.660 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): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Protein / Non-polymers , 3 types, 3 molecules ER

#4: Antibody scFv16


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein Sphingosine 1-phosphate receptor 2 / S1P receptor 2 / S1P2 / Endothelial differentiation G-protein coupled receptor 5 / Sphingosine 1- ...S1P receptor 2 / S1P2 / Endothelial differentiation G-protein coupled receptor 5 / Sphingosine 1-phosphate receptor Edg-5 / S1P receptor Edg-5


Mass: 39902.824 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: S1PR2, EDG5 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: O95136
#6: Chemical ChemComp-S1P / (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate / sphingosine 1-phosphate


Mass: 379.472 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H38NO5P / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: Structure of S1PR2-heterotrimeric G13 signaling complex
Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Homo sapiens (human)9606HEK293S GnTI-
31Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.5
Details: 20 mM Hepes pH7.5, 150 mM NaCl, 0.001% L-MNG/0.0001% CHS, 0.0025% GDN
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMsodium chlorideNaCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: C-flat-1.2/1.3
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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 640483 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048923
ELECTRON MICROSCOPYf_angle_d0.72412083
ELECTRON MICROSCOPYf_dihedral_angle_d7.0525776
ELECTRON MICROSCOPYf_chiral_restr0.0471397
ELECTRON MICROSCOPYf_plane_restr0.0051519

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