7eo2: Difference between revisions
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==== | ==Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to FTY720p== | ||
<StructureSection load='7eo2' size='340' side='right'caption='[[7eo2]]' scene=''> | <StructureSection load='7eo2' size='340' side='right'caption='[[7eo2]], [[Resolution|resolution]] 2.89Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<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> | <table><tr><td colspan='2'>[[7eo2]] 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=7EO2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EO2 FirstGlance]. <br> | ||
</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=7eo2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eo2 OCA], [https://pdbe.org/7eo2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eo2 RCSB], [https://www.ebi.ac.uk/pdbsum/7eo2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eo2 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.89Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J89:[(2~{S})-2-azanyl-2-(hydroxymethyl)-4-(4-octylphenyl)butyl]+dihydrogen+phosphate'>J89</scene></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=7eo2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eo2 OCA], [https://pdbe.org/7eo2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eo2 RCSB], [https://www.ebi.ac.uk/pdbsum/7eo2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eo2 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/GBG2_HUMAN GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7eo2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Transducin 3D structures|Transducin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Z | [[Category: He Y]] | ||
[[Category: Ikuta T]] | |||
[[Category: Xu Z]] | |||