7eo4

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Current revision (13:33, 6 November 2024) (edit) (undo)
 
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==Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to BAF312==
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<StructureSection load='7eo4' size='340' side='right'caption='[[7eo4]]' scene=''>
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<StructureSection load='7eo4' size='340' side='right'caption='[[7eo4]], [[Resolution|resolution]] 2.86&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7eo4]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7EO4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EO4 FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7eo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eo4 OCA], [https://pdbe.org/7eo4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eo4 RCSB], [https://www.ebi.ac.uk/pdbsum/7eo4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eo4 ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.86&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J8C:1-[[4-[(~{E})-~{N}-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-~{C}-methyl-carbonimidoyl]-2-ethyl-phenyl]methyl]azetidine-3-carboxylic+acid'>J8C</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7eo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eo4 OCA], [https://pdbe.org/7eo4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eo4 RCSB], [https://www.ebi.ac.uk/pdbsum/7eo4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eo4 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[https://www.uniprot.org/uniprot/S1PR1_HUMAN S1PR1_HUMAN] G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization and bone homeostasis (By similarity). Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury.<ref>PMID:10982820</ref> <ref>PMID:11230698</ref> <ref>PMID:11583630</ref> <ref>PMID:11604399</ref> <ref>PMID:19286607</ref> <ref>PMID:22344443</ref> <ref>PMID:8626678</ref> <ref>PMID:9488656</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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 beta-arrestin. However, a structural basis of biased agonism remains elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of G(i)-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 beta-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(6.48) and the retained interaction between F265(6.44) and N307(7.49) are the key features of the beta-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.
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Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism.,Xu Z, Ikuta T, Kawakami K, Kise R, Qian Y, Xia R, Sun MX, Zhang A, Guo C, Cai XH, Huang Z, Inoue A, He Y Nat Chem Biol. 2022 Mar;18(3):281-288. doi: 10.1038/s41589-021-00930-3. Epub 2021 , Dec 22. PMID:34937912<ref>PMID:34937912</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7eo4" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Transducin 3D structures|Transducin 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Z-disk]]
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[[Category: He Y]]
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[[Category: Ikuta T]]
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[[Category: Inoue A]]
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[[Category: Xu Z]]

Current revision

Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to BAF312

PDB ID 7eo4

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