7fje: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7fje]] is a 8 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=7FJE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FJE FirstGlance]. <br> | <table><tr><td colspan='2'>[[7fje]] is a 8 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=7FJE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FJE FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene></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]] 3Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</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=7fje FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7fje OCA], [https://pdbe.org/7fje PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7fje RCSB], [https://www.ebi.ac.uk/pdbsum/7fje PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7fje ProSAT]</span></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=7fje FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7fje OCA], [https://pdbe.org/7fje PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7fje RCSB], [https://www.ebi.ac.uk/pdbsum/7fje PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7fje ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[https://www.uniprot.org/uniprot/CD3Z_HUMAN CD3Z_HUMAN] Defects in CD247 are the cause of immunodeficiency due to defect in CD3-zeta (CD3ZID) [MIM:[https://omim.org/entry/610163 610163]. An immunological deficiency characterized by T-cells impaired immune response to alloantigens, tetanus toxoid and mitogens.<ref>PMID:16672702</ref> | |||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/CD3Z_HUMAN CD3Z_HUMAN] Probable role in assembly and expression of the TCR complex as well as signal transduction upon antigen triggering. | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Cholesterol molecules specifically bind to the resting alphabetaTCR to inhibit cytoplasmic CD3zeta ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms of cholesterol-mediated inhibition of TCR-CD3 and its activation remain unclear. Here, we present cryoelectron microscopy structures of cholesterol- and cholesterol sulfate (CS)-inhibited TCR-CD3 complexes and an auto-active TCR-CD3 variant. The structures reveal that cholesterol molecules act like a latch to lock CD3zeta into an inactive conformation in the membrane. Mutations impairing binding of cholesterol molecules to the tunnel result in the movement of the proximal C terminus of the CD3zeta transmembrane helix, thereby activating the TCR-CD3 complex in human cells. Together, our data reveal the structural basis of TCR inhibition by cholesterol, illustrate how the cholesterol-binding tunnel is allosterically coupled to TCR triggering, and lay a foundation for the development of immunotherapies through directly targeting the TCR-CD3 complex. | Cholesterol molecules specifically bind to the resting alphabetaTCR to inhibit cytoplasmic CD3zeta ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms of cholesterol-mediated inhibition of TCR-CD3 and its activation remain unclear. Here, we present cryoelectron microscopy structures of cholesterol- and cholesterol sulfate (CS)-inhibited TCR-CD3 complexes and an auto-active TCR-CD3 variant. The structures reveal that cholesterol molecules act like a latch to lock CD3zeta into an inactive conformation in the membrane. Mutations impairing binding of cholesterol molecules to the tunnel result in the movement of the proximal C terminus of the CD3zeta transmembrane helix, thereby activating the TCR-CD3 complex in human cells. Together, our data reveal the structural basis of TCR inhibition by cholesterol, illustrate how the cholesterol-binding tunnel is allosterically coupled to TCR triggering, and lay a foundation for the development of immunotherapies through directly targeting the TCR-CD3 complex. | ||
Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility.,Chen Y, Zhu Y, Li X, Gao W, Zhen Z, Dong, Huang B, Ma Z, Zhang A, Song X, Ma Y, Guo C, Zhang F, Huang Z Mol Cell. 2022 Apr 7;82(7):1278-1287.e5. doi: 10.1016/j.molcel.2022.02.017. Epub , 2022 Mar 9. PMID:35271814<ref>PMID:35271814</ref> | Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility.,Chen Y, Zhu Y, Li X, Gao W, Zhen Z, Dong D, Huang B, Ma Z, Zhang A, Song X, Ma Y, Guo C, Zhang F, Huang Z Mol Cell. 2022 Apr 7;82(7):1278-1287.e5. doi: 10.1016/j.molcel.2022.02.017. Epub , 2022 Mar 9. PMID:35271814<ref>PMID:35271814</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 7fje" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7fje" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[CD3 3D structures|CD3 3D structures]] | |||
*[[T-cell receptor 3D structures|T-cell receptor 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||