View source for 8g94


==Structure of CD69-bound S1PR1 coupled to heterotrimeric Gi==
<StructureSection load='8g94' size='340' side='right'caption='[[8g94]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8g94]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G94 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G94 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.15&#8491;</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=8g94 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g94 OCA], [https://pdbe.org/8g94 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g94 RCSB], [https://www.ebi.ac.uk/pdbsum/8g94 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g94 ProSAT]</span></td></tr>
</table>
== Function ==
[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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== Publication Abstract from PubMed ==
The activation of Sphingosine-1-phosphate receptor 1 (S1PR1) by S1P promotes lymphocyte egress from lymphoid organs, a process critical for immune surveillance and T cell effector activity. Multiple drugs that inhibit S1PR1 function are in use clinically for the treatment of autoimmune diseases. Cluster of Differentiation 69 (CD69) is an endogenous negative regulator of lymphocyte egress that interacts with S1PR1 in cis to facilitate internalization and degradation of the receptor. The mechanism by which CD69 causes S1PR1 internalization has been unclear. Moreover, although there are numerous class A GPCR structures determined with different small molecule agonists bound, it remains unknown whether a transmembrane protein per se can act as a class A GPCR agonist. Here, we present the cryo-EM structure of CD69-bound S1PR1 coupled to the heterotrimeric G(i) complex. The transmembrane helix (TM) of one protomer of CD69 homodimer contacts the S1PR1-TM4. This interaction allosterically induces the movement of S1PR1-TMs 5-6, directly activating the receptor to engage the heterotrimeric G(i). Mutations in key residues at the interface affect the interactions between CD69 and S1PR1, as well as reduce the receptor internalization. Thus, our structural findings along with functional analyses demonstrate that CD69 acts in cis as a protein agonist of S1PR1, thereby promoting G(i)-dependent S1PR1 internalization, loss of S1P gradient sensing, and inhibition of lymphocyte egress.

Transmembrane protein CD69 acts as an S1PR1 agonist.,Chen H, Qin Y, Chou M, Cyster JG, Li X Elife. 2023 Apr 11;12:e88204. doi: 10.7554/eLife.88204. PMID:37039481<ref>PMID:37039481</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8g94" style="background-color:#fffaf0;"></div>

==See Also==
*[[Transducin 3D structures|Transducin 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Chen H]]
[[Category: Li X]]