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- EMDB-31344: Cryo-EM structure of siponimod -bound Sphingosine-1-phosphate rec... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-31344 | |||||||||
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Title | Cryo-EM structure of siponimod -bound Sphingosine-1-phosphate receptor 5 in complex with Gi protein | |||||||||
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Function / homology | ![]() sphingosine-1-phosphate receptor activity / Lysosphingolipid and LPA receptors / regulation of metabolic process / regulation of neuron differentiation / 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 mitotic spindle organization ...sphingosine-1-phosphate receptor activity / Lysosphingolipid and LPA receptors / regulation of metabolic process / regulation of neuron differentiation / 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 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 / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / response to peptide hormone / 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 / 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 / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / 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 / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / membrane => GO:0016020 / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
![]() | Yuan Y / Jia GW / Shao ZH / Su ZM | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition. Authors: Yuan Yuan / Guowen Jia / Chao Wu / Wei Wang / Lin Cheng / Qian Li / Ziyan Li / Kaidong Luo / Shengyong Yang / Wei Yan / Zhaoming Su / Zhenhua Shao / ![]() Abstract: Sphingosine-1-phosphate (S1P) is an important bioactive lipid molecule in cell membrane metabolism and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, ...Sphingosine-1-phosphate (S1P) is an important bioactive lipid molecule in cell membrane metabolism and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, physiological homeostasis, and pathogenic processes in various organs. S1PRs are lipid-sensing receptors and are therapeutic targets for drug development, including potential treatment of COVID-19. Herein, we present five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. Our structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling. | |||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 5.2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.3 KB 15.3 KB | Display Display | ![]() |
Images | ![]() | 47.7 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7ew1MC ![]() 7evyC ![]() 7evzC ![]() 7ew0C ![]() 7ew7C M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : Sphingosine-1-phosphate receptor 5 complexed with Gi protein with...
Entire | Name: Sphingosine-1-phosphate receptor 5 complexed with Gi protein with bound siponimod |
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Components |
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-Supramolecule #1: Sphingosine-1-phosphate receptor 5 complexed with Gi protein with...
Supramolecule | Name: Sphingosine-1-phosphate receptor 5 complexed with Gi protein with bound siponimod type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 39.141793 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MHHHHLEVLF QGPGSSGSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSA SQDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT G YLSCCRFL ...String: MHHHHLEVLF QGPGSSGSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSA SQDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT G YLSCCRFL DDNQIVTSSG DTTCALWDIE TGQQTTTFTG HTGDVMSLSL APDTRLFVSG ACDASAKLWD VREGMCRQTF TG HESDINA ICFFPNGNAF ATGSDDATCR LFDLRADQEL MTYSHDNIIC GITSVSFSKS GRLLLAGYDD FNCNVWDALK ADR AGVLAG HDNRVSCLGV TDDGMAVATG SWDSFLKIWN |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 40.415031 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF |
-Macromolecule #4: scFv16
Macromolecule | Name: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 28.636793 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAAENLYFQ GHHHHHHHH |
-Macromolecule #5: Sphingosine 1-phosphate receptor 5
Macromolecule | Name: Sphingosine 1-phosphate receptor 5 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 42.630242 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MKTIIALSYI FCLVFADYKD DDDKMGENLY FQGMESGLLR PAPVSEVIVL HYNYTGKLRG ARYQPGAGLR ADAVVCLAVC AFIVLENLA VLLVLGRHPR FHAPMFLLLG SLTLSDLLAG AAYAANILLS GPLTLKLSPA LWFAREGGVF VALTASVLSL L AIALERSL ...String: MKTIIALSYI FCLVFADYKD DDDKMGENLY FQGMESGLLR PAPVSEVIVL HYNYTGKLRG ARYQPGAGLR ADAVVCLAVC AFIVLENLA VLLVLGRHPR FHAPMFLLLG SLTLSDLLAG AAYAANILLS GPLTLKLSPA LWFAREGGVF VALTASVLSL L AIALERSL TMARRGPAPV SSRGRTLAMA AAAWGVSLLL GLLPALGWNC LGRLDACSTV LPLYAKAYVL FCVLAFVGIL AA ICALYAR IYCQVRANAR RLPARPGTAG TTSTRARRKP RSLALLRTLS VVLLAFVACW GPLFLLLLLD VACPARTCPV LLQ ADPFLG LAMANSLLNP IIYTLTNRDL RHALLRLVCC GRHSCGRDPS GSQQSASAAE AENLYFQGHH HHHHHHHH |
-Macromolecule #6: 1-[[4-[(~{E})-~{N}-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]metho...
Macromolecule | Name: 1-[[4-[(~{E})-~{N}-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-~{C}-methyl-carbonimidoyl]-2-ethyl-phenyl]methyl]azetidine-3-carboxylic acid type: ligand / ID: 6 / Number of copies: 1 / Formula: J8C |
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Molecular weight | Theoretical: 516.595 Da |
Chemical component information | ![]() ChemComp-J8C: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 56.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 366479 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |