[English] 日本語
Yorodumi- PDB-7wf7: Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound ... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7wf7 | ||||||
---|---|---|---|---|---|---|---|
Title | Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to S1P | ||||||
Components |
| ||||||
Keywords | MEMBRANE 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 / 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 / sphingosine-1-phosphate receptor activity / sphingolipid binding / blood vessel maturation / 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 / lamellipodium assembly / negative regulation of stress fiber 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 / G protein-coupled serotonin receptor binding / regulation of cell adhesion / 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 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 / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / neuron differentiation / 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 / 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 / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / chemotaxis / cell migration / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / actin cytoskeleton organization / G alpha (q) signalling events / angiogenesis / Interleukin-4 and Interleukin-13 signaling / Ras protein signal transduction / cell population proliferation / Potential therapeutics for SARS / Extra-nuclear estrogen signaling / cell adhesion / endosome / positive regulation of cell migration / cell cycle / membrane raft / G protein-coupled receptor signaling pathway Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å | ||||||
Authors | He, Y. / Xu, Z. | ||||||
Funding support | China, 1items
| ||||||
Citation | Journal: 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 |
|
-Structure visualization
Movie |
Movie viewer |
---|---|
Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7wf7.cif.gz | 194.3 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb7wf7.ent.gz | 155.4 KB | Display | PDB format |
PDBx/mmJSON format | 7wf7.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/wf/7wf7 ftp://data.pdbj.org/pub/pdb/validation_reports/wf/7wf7 | HTTPS FTP |
---|
-Related structure data
Related structure data | 32461MC 7eo2C 7eo4C M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-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.) Homo sapiens (human) / Gene: GNAI1 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: P63096 |
---|---|
#3: Protein | 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 | 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 |
-Protein / Antibody / Non-polymers , 3 types, 3 molecules AE
#1: Protein | 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 | 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-S1P / ( |
-Details
Has ligand of interest | N |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: 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 solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE / Humidity: 98 % |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: OTHER / Nominal defocus max: 2300 nm / Nominal defocus min: 1200 nm / Calibrated defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm |
Image recording | Electron dose: 60 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 |
EM imaging optics | Energyfilter name: GIF Bioquantum |
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: 93 % / High resolution: 2.83 Å / Num. of intensities measured: 1590 / Num. of structure factors: 325 / Phase error rejection criteria: 20 / Rmerge: 0.198 |
-Processing
EM software |
| |||||||||
---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: NONE | |||||||||
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 500000 / Symmetry type: POINT | |||||||||
Atomic model building | B value: 143 / Protocol: AB INITIO MODEL / Space: REAL | |||||||||
Atomic model building | PDB-ID: 6VMS Pdb chain-ID: A |