Human leukocyte antigen class I peptide-binding groove (HLA-I groove)

The Human leukocyte antigen class I (HLA-I) peptide-binding groove is a specialized structural domain formed by the alpha-1 and alpha-2 helices of the HLA heavy chain [Bjorkman, P. J., et al. (1987) Nature]. Its primary biological function is to capture and display short endogenous peptides, typically 8 to 10 amino acids in length, on the surface of nucleated cells for recognition by CD8+ T-cell receptors [Rock, K. L., et al. (2016) Cell]. This presentation is a cornerstone of immune surveillance, enabling the immune system to identify and destroy cells harboring viral infections or malignant mutations. In modern oncology, the groove is a critical target for TCR-based therapies and bispecific T-cell engagers that recognize specific peptide-HLA complexes, such as those involving neoantigens or cancer-testis antigens [UniProt P04439]. Beyond its role in natural immunity, the HLA-I groove is a site of significant pharmacological interest due to its involvement in idiosyncratic drug reactions. Certain small molecules, most notably the antiretroviral drug Abacavir, can bind non-covalently within the groove (specifically the F-pocket of HLA-B*57:01), thereby altering the repertoire of presented self-peptides [Illing, P. T., et al. (2012) Nature]. This alteration can lead to the activation of self-reactive T cells, resulting in severe systemic hypersensitivity. Consequently, the structural and polymorphic nature of the HLA-I groove is a vital consideration in both the design of targeted immunotherapies and the assessment of drug safety profiles.

Other names

MHC class I peptide-binding cleftHLA class I binding pocketMajor histocompatibility complex class I grooveHLA-I peptide-binding site

Presentation of endogenous or exogenous peptides to CD8+ T-cell receptors to initiate an adaptive immune response; direct binding by small molecules can alter the peptide-binding specificity and trigger immune-mediated toxicity.