View source for 8rro


==G12V-TCR complex with HLA-A3==
<StructureSection load='8rro' size='340' side='right'caption='[[8rro]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8rro]] is a 40 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=8RRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8RRO 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]] 3.5&#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=8rro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8rro OCA], [https://pdbe.org/8rro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8rro RCSB], [https://www.ebi.ac.uk/pdbsum/8rro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8rro ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that are targetable by adoptive T-cell therapy in metastatic diseases. To expand mutant KRAS-specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T-cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen ((7)VVVGAVGVGK(16)) using a vaccination approach with transgenic mice expressing HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not WT KRAS peptides. To investigate the molecular basis for neoantigen recognition by this TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3beta and CDR1beta formed a hydrophobic pocket to interact with p6 Val of the G12V but not the WT KRAS peptide. To improve the tumor sensitivity of this TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding avidity to HLA-A3 (G12V) but did not sufficiently improve T-cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations.

Identification and structural characterization of a mutant KRAS-G12V specific TCR restricted by HLA-A3.,Sim MJW, Hanada KI, Stotz Z, Yu Z, Lu J, Brennan P, Quastel M, Gillespie GM, Long EO, Yang JC, Sun PD Eur J Immunol. 2024 Sep;54(9):e2451079. doi: 10.1002/eji.202451079. Epub 2024 Jul , 18. PMID:39030753<ref>PMID:39030753</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8rro" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Sim MJW]]
[[Category: Sun PD]]