8ih4: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal Structure of Intracellular B30.2 Domain of BTN2A2 Mutant== | |||
<StructureSection load='8ih4' size='340' side='right'caption='[[8ih4]], [[Resolution|resolution]] 2.12Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8ih4]] is a 2 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=8IH4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IH4 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.12Å</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=8ih4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ih4 OCA], [https://pdbe.org/8ih4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ih4 RCSB], [https://www.ebi.ac.uk/pdbsum/8ih4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ih4 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BT2A2_HUMAN BT2A2_HUMAN] Inhibits the proliferation of CD4 and CD8 T-cells activated by anti-CD3 antibodies, T-cell metabolism and IL2 and IFNG secretion. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In both cancer and infections, diseased cells are presented to human Vgamma9Vdelta2 T cells through an 'inside out' signalling process whereby structurally diverse phosphoantigen (pAg) molecules are sensed by the intracellular domain of butyrophilin BTN3A1(1-4). Here we show how-in both humans and alpaca-multiple pAgs function as 'molecular glues' to promote heteromeric association between the intracellular domains of BTN3A1 and the structurally similar butyrophilin BTN2A1. X-ray crystallography studies visualized that engagement of BTN3A1 with pAgs forms a composite interface for direct binding to BTN2A1, with various pAg molecules each positioned at the centre of the interface and gluing the butyrophilins with distinct affinities. Our structural insights guided mutagenesis experiments that led to disruption of the intracellular BTN3A1-BTN2A1 association, abolishing pAg-mediated Vgamma9Vdelta2 T cell activation. Analyses using structure-based molecular-dynamics simulations, (19)F-NMR investigations, chimeric receptor engineering and direct measurement of intercellular binding force revealed how pAg-mediated BTN2A1 association drives BTN3A1 intracellular fluctuations outwards in a thermodynamically favourable manner, thereby enabling BTN3A1 to push off from the BTN2A1 ectodomain to initiate T cell receptor-mediated gammadelta T cell activation. Practically, we harnessed the molecular-glue model for immunotherapeutics design, demonstrating chemical principles for developing both small-molecule activators and inhibitors of human gammadelta T cell function. | |||
Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vgamma9Vdelta2 T cells.,Yuan L, Ma X, Yang Y, Qu Y, Li X, Zhu X, Ma W, Duan J, Xue J, Yang H, Huang JW, Yi S, Zhang M, Cai N, Zhang L, Ding Q, Lai K, Liu C, Zhang L, Liu X, Yao Y, Zhou S, Li X, Shen P, Chang Q, Malwal SR, He Y, Li W, Chen C, Chen CC, Oldfield E, Guo RT, Zhang Y Nature. 2023 Sep 6. doi: 10.1038/s41586-023-06525-3. PMID:37674084<ref>PMID:37674084</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8ih4" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | |||
[[Category: Chen CC]] | |||
[[Category: Guo RT]] | |||
[[Category: Yang YY]] | |||
[[Category: Yi SM]] | |||
[[Category: Zhang MT]] | |||
[[Category: Zhang YH]] | |||
Revision as of 21:16, 20 September 2023
Crystal Structure of Intracellular B30.2 Domain of BTN2A2 MutantCrystal Structure of Intracellular B30.2 Domain of BTN2A2 Mutant
Structural highlights
FunctionBT2A2_HUMAN Inhibits the proliferation of CD4 and CD8 T-cells activated by anti-CD3 antibodies, T-cell metabolism and IL2 and IFNG secretion. Publication Abstract from PubMedIn both cancer and infections, diseased cells are presented to human Vgamma9Vdelta2 T cells through an 'inside out' signalling process whereby structurally diverse phosphoantigen (pAg) molecules are sensed by the intracellular domain of butyrophilin BTN3A1(1-4). Here we show how-in both humans and alpaca-multiple pAgs function as 'molecular glues' to promote heteromeric association between the intracellular domains of BTN3A1 and the structurally similar butyrophilin BTN2A1. X-ray crystallography studies visualized that engagement of BTN3A1 with pAgs forms a composite interface for direct binding to BTN2A1, with various pAg molecules each positioned at the centre of the interface and gluing the butyrophilins with distinct affinities. Our structural insights guided mutagenesis experiments that led to disruption of the intracellular BTN3A1-BTN2A1 association, abolishing pAg-mediated Vgamma9Vdelta2 T cell activation. Analyses using structure-based molecular-dynamics simulations, (19)F-NMR investigations, chimeric receptor engineering and direct measurement of intercellular binding force revealed how pAg-mediated BTN2A1 association drives BTN3A1 intracellular fluctuations outwards in a thermodynamically favourable manner, thereby enabling BTN3A1 to push off from the BTN2A1 ectodomain to initiate T cell receptor-mediated gammadelta T cell activation. Practically, we harnessed the molecular-glue model for immunotherapeutics design, demonstrating chemical principles for developing both small-molecule activators and inhibitors of human gammadelta T cell function. Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vgamma9Vdelta2 T cells.,Yuan L, Ma X, Yang Y, Qu Y, Li X, Zhu X, Ma W, Duan J, Xue J, Yang H, Huang JW, Yi S, Zhang M, Cai N, Zhang L, Ding Q, Lai K, Liu C, Zhang L, Liu X, Yao Y, Zhou S, Li X, Shen P, Chang Q, Malwal SR, He Y, Li W, Chen C, Chen CC, Oldfield E, Guo RT, Zhang Y Nature. 2023 Sep 6. doi: 10.1038/s41586-023-06525-3. PMID:37674084[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||