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- PDB-7eo4: Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound ... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7eo4 | ||||||
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Title | Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to BAF312 | ||||||
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![]() | MEMBRANE PROTEIN / GPCR | ||||||
Function / homology | ![]() cardiac muscle tissue growth involved in heart morphogenesis / sphingolipid binding / blood vessel maturation / sphingosine-1-phosphate receptor activity / Lysosphingolipid and LPA receptors / T cell migration / endothelial cell differentiation / heart trabecula morphogenesis / regulation of metabolic process / regulation of bone mineralization ...cardiac muscle tissue growth involved in heart morphogenesis / sphingolipid binding / blood vessel maturation / sphingosine-1-phosphate receptor activity / Lysosphingolipid and LPA receptors / T cell migration / endothelial cell differentiation / heart trabecula morphogenesis / regulation of metabolic process / regulation of bone mineralization / sphingosine-1-phosphate receptor signaling pathway / leukocyte chemotaxis / regulation of bone resorption / positive regulation of positive chemotaxis / negative regulation of stress fiber assembly / lamellipodium assembly / transmission of nerve impulse / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / regulation of cell adhesion / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor activity / G protein-coupled receptor binding / positive regulation of smooth muscle cell proliferation / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / neuron differentiation / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / brain development / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / chemotaxis / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / cell migration / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / actin cytoskeleton organization / G alpha (s) signalling events / G alpha (q) signalling events / angiogenesis / Interleukin-4 and Interleukin-13 signaling / cell population proliferation / Ras protein signal transduction / Potential therapeutics for SARS / Extra-nuclear estrogen signaling / cell adhesion / endosome / positive regulation of cell migration / membrane raft / cell cycle / G protein-coupled receptor signaling pathway Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.86 Å | ||||||
![]() | He, Y. / Xu, Z. / Ikuta, T. / Inoue, A. | ||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 197.5 KB | Display | ![]() |
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PDB format | ![]() | 157.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 887.8 KB | Display | ![]() |
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Full document | ![]() | 892.3 KB | Display | |
Data in XML | ![]() | 37.7 KB | Display | |
Data in CIF | ![]() | 57.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 31226MC ![]() 7eo2C ![]() 7wf7C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD
#2: Protein | Mass: 40445.059 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#3: Protein | Mass: 37915.496 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#4: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Protein / Antibody / Non-polymers , 3 types, 3 molecules AE![](data/chem/img/J8C.gif)
![](data/chem/img/J8C.gif)
#1: Protein | Mass: 42898.754 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#5: Antibody | Mass: 26293.299 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#6: Chemical | ChemComp-J8C / |
-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: 3D ARRAY / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: S1PR1/Gi complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
EM diffraction | Camera length: 800 mm |
EM diffraction shell | Resolution: 3→5.5 Å / Fourier space coverage: 93.2 % / Multiplicity: 2.5 / Num. of structure factors: 244 / Phase residual: 13.5 ° |
EM diffraction stats | Fourier 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 |
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CTF correction | Type: NONE | |||||||||
3D reconstruction | Resolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 500000 / Symmetry type: POINT | |||||||||
Atomic model building | Protocol: OTHER / Space: REAL | |||||||||
Atomic model building | PDB-ID: 6VMS Pdb chain-ID: A |