Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

ABSTRACT: The inherent cross-reactivity of the T cell receptor (TCR) is balanced by high specificity, which often manifests in confounding ways not easily interpretable from static structures. We show here that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen derived from mutant PIK3CA and its wild-type (WT) counterpart emerges from motions within the HLA binding groove that vary with the identity of the peptide's first primary anchor. The motions form a dynamic gate that in the complex with the WT peptide impedes a large conformational change required for TCR binding. The more rigid neoantigen is insusceptible to this limiting dynamic, and with the gate open, is able to transit its central tryptophan residue underneath the peptide backbone to the contralateral

SUBMITTER: Ma J 

PROVIDER: S-EPMC11160895 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature