7Z50

Structure of the highly diabetogenic 4.1-T cell receptor targeting a hybrid insulin peptide bound to I-Ag7.

Summary for 7Z50

• Entry DOI: 10.2210/pdb7z50/pdb
• Related: 7QHP
• Descriptor: H-2 class II histocompatibility antigen, A-D alpha chain, H2-Ab1 protein, 4.1 TCR beta chain, ... (10 entities in total)
• Functional Keywords: diabetes, t cell receptor, murine mhc class ii, hybrid insulin peptide, immune system
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 10
• Total formula weight: 204265.46

Authors

Lopez-Sagaseta, J.,Erausquin, E. (deposition date: 2022-03-06, release date: 2022-07-20, Last modification date: 2024-10-16)

Primary citation

Erausquin, E.,Serra, P.,Parras, D.,Santamaria, P.,Lopez-Sagaseta, J.
Structural plasticity in I-A g7 links autoreactivity to hybrid insulin peptides in type I diabetes.
Front Immunol, 13:924311-924311, 2022

PubMed Abstract: We recently provided evidence for promiscuous recognition of several different hybrid insulin peptides (HIPs) by the highly diabetogenic, I-A-restricted 4.1-T cell receptor (TCR). To understand the structural determinants of this phenomenon, we solved the structure of an agonistic HIP/I-A complex, both in isolation as well as bound to the 4.1-TCR. We find that HIP promiscuity of the 4.1-TCR is dictated, on the one hand, by an amino acid sequence pattern that ensures I-A binding and, on the other hand, by the presence of three acidic residues at positions P5, P7 and P8 that favor an optimal engagement by the 4.1-TCR's complementary determining regions. Surprisingly, comparison of the TCR-bound and unbound HIP/I-A structures reveals that 4.1-TCR binding triggers several novel and unique structural motions in both the I-A molecule and the peptide that are essential for docking. This observation indicates that the type 1 diabetes-associated I-A molecule is structurally malleable and that this plasticity allows the recognition of multiple peptides by individual TCRs that would otherwise be unable to do so.

PubMed: 35967292
DOI: 10.3389/fimmu.2022.924311

Experimental method

X-RAY DIFFRACTION (2.65 Å)