Human major histocompatibility complex class I (HLA-I)

The Human Major Histocompatibility Complex class I (MHC-I) peptide-binding groove is a specialized structural cleft formed by the alpha-1 and alpha-2 domains of the MHC-I heavy chain, which non-covalently binds short peptides (typically 8-10 amino acids) for presentation on the cell surface (Bjorkman et al., 1987, Nature). This mechanism is fundamental to the adaptive immune system, enabling CD8+ cytotoxic T cells to survey the intracellular proteome for signs of viral infection or malignant transformation (Janeway et al., 2001, Immunobiology). In modern oncology, the peptide-MHC complex is a primary target for TCR-engineered T cells and bispecific engagers like tebentafusp, which are designed to recognize specific tumor-associated antigens presented within the groove (Nathan et al., 2021, NEJM). Beyond its role in antigen presentation, the groove can inadvertently bind certain small-molecule drugs, such as abacavir, which alters the shape of the pocket and the selection of presented self-peptides, leading to severe systemic hypersensitivity reactions (Illing et al., 2012, Nature). Due to the extreme polymorphism of HLA genes, the specific architecture of the binding groove varies significantly between individuals, making HLA typing a prerequisite for many targeted immunotherapies and organ transplants (Wieczorek et al., 2017, Frontiers in Immunology).

Other names

MHC class I peptide-binding grooveHuman leukocyte antigen class IMHC-IHLA class IMHC-I peptide-binding pocket

Presentation of intracellularly derived peptides to CD8+ cytotoxic T lymphocytes to trigger immune recognition and response; also acts as a binding site for certain small molecules that can alter the repertoire of presented peptides.