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- PDB-7eo4: Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound ... -

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Basic information

Entry
Database: PDB / ID: 7eo4
TitleCryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to BAF312
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Sphingosine 1-phosphate receptor 1
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR
Function / homology
Function and homology information


cardiac muscle tissue growth involved in heart morphogenesis / sphingosine-1-phosphate receptor activity / sphingolipid binding / blood vessel maturation / Lysosphingolipid and LPA receptors / endothelial cell differentiation / heart trabecula morphogenesis / regulation of bone mineralization / sphingosine-1-phosphate receptor signaling pathway / regulation of metabolic process ...cardiac muscle tissue growth involved in heart morphogenesis / sphingosine-1-phosphate receptor activity / sphingolipid binding / blood vessel maturation / Lysosphingolipid and LPA receptors / endothelial cell differentiation / heart trabecula morphogenesis / regulation of bone mineralization / sphingosine-1-phosphate receptor signaling pathway / regulation of metabolic process / leukocyte chemotaxis / regulation of bone resorption / positive regulation of positive chemotaxis / lamellipodium assembly / negative regulation of stress fiber assembly / transmission of nerve impulse / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cell adhesion / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / positive regulation of smooth muscle cell proliferation / brain development / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / neuron differentiation / 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 / response to peptide hormone / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / chemotaxis / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / cell migration / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / midbody / G alpha (i) signalling events / actin cytoskeleton organization / fibroblast proliferation / G alpha (s) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Interleukin-4 and Interleukin-13 signaling / angiogenesis / G alpha (q) signalling events / Ras protein signal transduction / Potential therapeutics for SARS / cell population proliferation / Extra-nuclear estrogen signaling / cell adhesion / endosome / positive regulation of cell migration / G protein-coupled receptor signaling pathway / membrane raft
Similarity search - Function
EDG-1 sphingosine 1-phosphate receptor / Sphingosine 1-phosphate receptor / G-protein alpha subunit, group I / 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-1 sphingosine 1-phosphate receptor / Sphingosine 1-phosphate receptor / G-protein alpha subunit, group I / 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-J8C / Sphingosine 1-phosphate receptor 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(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.86 Å
AuthorsHe, Y. / Xu, Z. / Ikuta, T. / Inoue, A.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32070048 China
CitationJournal: Nat Chem Biol / Year: 2022
Title: Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism.
Authors: Zhenmei Xu / Tatsuya Ikuta / Kouki Kawakami / Ryoji Kise / Yu Qian / Ruixue Xia / Ming-Xia Sun / Anqi Zhang / Changyou Guo / Xue-Hui Cai / Zhiwei Huang / Asuka Inoue / Yuanzheng He /
Abstract: Sphingosine-1-phosphate receptor 1 (S1PR1) is a master regulator of lymphocyte egress from the lymph node and an established drug target for multiple sclerosis (MS). Mechanistically, therapeutic ...Sphingosine-1-phosphate receptor 1 (S1PR1) is a master regulator of lymphocyte egress from the lymph node and an established drug target for multiple sclerosis (MS). Mechanistically, therapeutic S1PR1 modulators activate the receptor yet induce sustained internalization through a potent association with β-arrestin. However, a structural basis of biased agonism remains elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of G-bound S1PR1 in complex with S1P, fingolimod-phosphate (FTY720-P) and siponimod (BAF312). In combination with functional assays and molecular dynamics (MD) studies, we reveal that the β-arrestin-biased ligands direct a distinct activation path in S1PR1 through the extensive interplay between the PIF and the NPxxY motifs. Specifically, the intermediate flipping of W269 and the retained interaction between F265 and N307 are the key features of the β-arrestin bias. We further identify ligand-receptor interactions accounting for the S1PR subtype specificity of BAF312. These structural insights provide a rational basis for designing novel signaling-biased S1PR modulators.
History
DepositionApr 21, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 5, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Nov 6, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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  • Deposited structure unit
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  • Superimposition on EM map
  • EMDB-31226
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Sphingosine 1-phosphate receptor 1
B: Guanine nucleotide-binding protein G(i) subunit alpha-1
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)155,9306
Polymers155,4145
Non-polymers5171
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10030 Å2
ΔGint-60 kcal/mol
Surface area52730 Å2

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Components

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

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40445.059 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: P63096
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37915.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: P62873
#4: 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: Insect BA phytoplasma (bacteria) / References: UniProt: P59768

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

#1: Protein Sphingosine 1-phosphate receptor 1 / S1P receptor 1 / S1P1 / Endothelial differentiation G-protein coupled receptor 1 / Sphingosine 1- ...S1P receptor 1 / S1P1 / Endothelial differentiation G-protein coupled receptor 1 / Sphingosine 1-phosphate receptor Edg-1 / S1P receptor Edg-1


Mass: 42898.754 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: S1PR1, CHEDG1, EDG1 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: P21453
#5: Antibody scFv16


Mass: 26293.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Insect BA phytoplasma (bacteria)
#6: Chemical ChemComp-J8C / 1-[[4-[(~{E})-~{N}-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-~{C}-methyl-carbonimidoyl]-2-ethyl-phenyl]methyl]azetidine-3-carboxylic acid


Mass: 516.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H35F3N2O3

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 3D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: S1PR1/Gi complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Insect BA phytoplasma (bacteria)
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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM diffractionCamera length: 800 mm
EM diffraction shellResolution: 3→5.5 Å / Fourier space coverage: 93.2 % / Multiplicity: 2.5 / Num. of structure factors: 244 / Phase residual: 13.5 °
EM diffraction statsFourier space coverage: 90.3 % / High resolution: 2.83 Å / Num. of intensities measured: 1590 / Num. of structure factors: 325 / Phase error rejection criteria: 20 / Rmerge: 0.198

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Processing

EM software
IDNameCategory
7RELIONmodel fitting
9PHENIXmodel refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 500000 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Atomic model buildingPDB-ID: 6VMS

6vms


Pdb chain-ID: A / Accession code: 6VMS / Source name: PDB / Type: experimental model

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