8ek5: Difference between revisions
New page: '''Unreleased structure''' The entry 8ek5 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures |
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==Engineered scFv 10LH bound to PHOX2B/HLA-A24:02== | |||
<StructureSection load='8ek5' size='340' side='right'caption='[[8ek5]], [[Resolution|resolution]] 2.11Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8ek5]] is a 4 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=8EK5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8EK5 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]] 2.11Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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=8ek5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ek5 OCA], [https://pdbe.org/8ek5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ek5 RCSB], [https://www.ebi.ac.uk/pdbsum/8ek5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ek5 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/F6IR24_HUMAN F6IR24_HUMAN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Peptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed a PC-CAR targeting a neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of the PC-CAR-PHOX2B-HLA-A*24:02-beta(2)m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). This PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactive group, covering a combined global population frequency of up to 46.7%. Biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation, and CAR T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes. | |||
Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion.,Sun Y, Florio TJ, Gupta S, Young MC, Marshall QF, Garfinkle SE, Papadaki GF, Truong HV, Mycek E, Li P, Farrel A, Church NL, Jabar S, Beasley MD, Kiefel BR, Yarmarkovich M, Mallik L, Maris JM, Sgourakis NG Sci Immunol. 2023 Dec;8(90):eadj5792. doi: 10.1126/sciimmunol.adj5792. Epub 2023 , Dec 1. PMID:38039376<ref>PMID:38039376</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8ek5" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Florio TJ]] | |||
[[Category: Garfinkle SE]] | |||
[[Category: Sgourakis NG]] | |||
Latest revision as of 15:05, 23 October 2024
Engineered scFv 10LH bound to PHOX2B/HLA-A24:02Engineered scFv 10LH bound to PHOX2B/HLA-A24:02
Structural highlights
FunctionPublication Abstract from PubMedPeptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed a PC-CAR targeting a neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of the PC-CAR-PHOX2B-HLA-A*24:02-beta(2)m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). This PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactive group, covering a combined global population frequency of up to 46.7%. Biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation, and CAR T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes. Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion.,Sun Y, Florio TJ, Gupta S, Young MC, Marshall QF, Garfinkle SE, Papadaki GF, Truong HV, Mycek E, Li P, Farrel A, Church NL, Jabar S, Beasley MD, Kiefel BR, Yarmarkovich M, Mallik L, Maris JM, Sgourakis NG Sci Immunol. 2023 Dec;8(90):eadj5792. doi: 10.1126/sciimmunol.adj5792. Epub 2023 , Dec 1. PMID:38039376[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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