8SBL

Structure of HLA-A*24:02 in complex with peptide, LYLPVRVLI

Summary for 8SBL

• Entry DOI: 10.2210/pdb8sbl/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, LEU-TYR-LEU-PRO-VAL-ARG-VAL-LEU-ILE (3 entities in total)
• Functional Keywords: major histocompatibility complex (mhc), immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 181730.46

Authors

Mallik, L.,Young, M.C.,Sgourakis, N.G. (deposition date: 2023-04-03, release date: 2023-12-06, Last modification date: 2024-10-16)

Primary citation

Sun, Y.,Florio, T.J.,Gupta, S.,Young, M.C.,Marshall, Q.F.,Garfinkle, S.E.,Papadaki, G.F.,Truong, H.V.,Mycek, E.,Li, P.,Farrel, A.,Church, N.L.,Jabar, S.,Beasley, M.D.,Kiefel, B.R.,Yarmarkovich, M.,Mallik, L.,Maris, J.M.,Sgourakis, N.G.
Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion.
Sci Immunol, 8:eadj5792-eadj5792, 2023

PubMed Abstract: 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-βm 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.

PubMed: 38039376
DOI: 10.1126/sciimmunol.adj5792

Experimental method

X-RAY DIFFRACTION (3 Å)