8EK5

Engineered scFv 10LH bound to PHOX2B/HLA-A24:02

8EK5 の概要

• エントリーDOI: 10.2210/pdb8ek5/pdb
• 分子名称: MHC class I antigen, Beta-2-microglobulin, Paired mesoderm homeobox protein 2B peptide, ... (7 entities in total)
• 機能のキーワード: neuroblastoma, phox2b, antitumor protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 95135.66

構造登録者

Garfinkle, S.E.,Florio, T.J.,Sgourakis, N.G. (登録日: 2022-09-20, 公開日: 2023-12-06, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.11 Å)