7RK7

The complex between TIL 1383i TCR and human Class I MHC HLA-A2 with the bound Tyrosinase(369-377)(N371D) nonameric peptide

Summary for 7RK7

• Entry DOI: 10.2210/pdb7rk7/pdb
• Descriptor: HLA class I histocompatibility antigen, A alpha chain, Beta-2-microglobulin, Tyrosinase peptide, ... (6 entities in total)
• Functional Keywords: tcr, class i major histocompatibility complex, hla-a*02, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 97039.78

Authors

Singh, N.K.,Davancaze, L.M.,Arbuiso, A.,Weiss, L.I.,Keller, G.L.J.,Baker, B.M. (deposition date: 2021-07-22, release date: 2022-11-02, Last modification date: 2025-10-08)

Primary citation

Singh, N.K.,Alonso, J.A.,Devlin, J.R.,Keller, G.L.J.,Gray, G.I.,Chiranjivi, A.K.,Foote, S.G.,Landau, L.M.,Arbuiso, A.G.,Weiss, L.I.,Rosenberg, A.M.,Hellman, L.M.,Nishimura, M.I.,Baker, B.M.
A class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry.
Nat Commun, 13:7189-7189, 2022

PubMed Abstract: MHC restriction, which describes the binding of TCRs from CD4 T cells to class II MHC proteins and TCRs from CD8 T cells to class I MHC proteins, is a hallmark of immunology. Seemingly rare TCRs that break this paradigm exist, but mechanistic insight into their behavior is lacking. TIL1383I is a prototypical class-mismatched TCR, cloned from a CD4 T cell but recognizing the tyrosinase tumor antigen presented by the class I MHC HLA-A2 in a fully functional manner. Here we find that TIL1383I binds this class I target with a highly atypical geometry. Despite unorthodox binding, TCR signaling, antigen specificity, and the ability to use CD8 are maintained. Structurally, a key feature of TIL1383I is an exceptionally long CDR3β loop that mediates functions that are traditionally performed separately by hypervariable and germline loops in canonical TCR structures. Our findings thus expand the range of known TCR binding geometries compatible with normal function and specificity, provide insight into the determinants of MHC restriction, and may help guide TCR selection and engineering for immunotherapy.

PubMed: 36424374
DOI: 10.1038/s41467-022-34896-0

Experimental method

X-RAY DIFFRACTION (2.54 Å)