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==Crystal structure of TIGIT in complexed with Ociperlimab, crystal form I== | |||
<StructureSection load='8jel' size='340' side='right'caption='[[8jel]], [[Resolution|resolution]] 2.45Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8jel]] is a 12 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=8JEL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JEL 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]] 2.45Å</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=8jel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jel OCA], [https://pdbe.org/8jel PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jel RCSB], [https://www.ebi.ac.uk/pdbsum/8jel PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jel ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TIGIT_HUMAN TIGIT_HUMAN] Binds with high affinity to the poliovirus receptor (PVR) which causes increased secretion of IL10 and decreased secretion of IL12B and suppresses T-cell activation by promoting the generation of mature immunoregulatory dendritic cells. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
TIGIT is mainly expressed on T cells and is an inhibitory checkpoint receptor that binds to its ligand PVR in the tumor microenvironment. Anti-TIGIT monoclonal antibodies (mAbs) such as Ociperlimab and Tiragolumab block the TIGIT-PVR interaction and are in clinical development. However, the molecular blockade mechanism of these mAbs remains elusive. Here, we report the crystal structures of TIGIT in complex with Ociperlimab_Fab and Tiragolumab_Fab revealing that both mAbs bind TIGIT with a large steric clash with PVR. Furthermore, several critical epitopic residues are identified. Interestingly, the binding affinity of Ociperlimab toward TIGIT increases approximately 17-fold when lowering the pH from 7.4 to 6.0. Our structure shows a strong electrostatic interaction between ASP103(HCDR3) and HIS76(TIGIT) explaining the pH-responsive mechanism of Ociperlimab. In contrast, Tiragolumab does not show an acidic pH-dependent binding enhancement. Our results provide valuable information that could help to improve the efficacy of therapeutic antibodies for cancer treatment. | |||
Structural insights into the unique pH-responsive characteristics of the anti-TIGIT therapeutic antibody Ociperlimab.,Sun J, Zhang X, Xue L, Cheng L, Zhang J, Chen X, Shen Z, Li K, Wang L, Huang C, Song J Structure. 2024 May 2;32(5):550-561.e5. doi: 10.1016/j.str.2024.02.009. Epub 2024 , Mar 8. PMID:38460520<ref>PMID:38460520</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Song | <div class="pdbe-citations 8jel" style="background-color:#fffaf0;"></div> | ||
[[Category: Sun | == References == | ||
[[Category: Zhang | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Song J]] | |||
[[Category: Sun J]] | |||
[[Category: Zhang XX]] | |||