Atomistic structure and dynamics of the human MHC-I peptide-loading complex

Significance The major histocompatibility complex class-I (MHC-I) peptide-loading complex (PLC) translocates cytosolic degradation products to the endoplasmic reticulum to load antigenic peptides onto MHC-I molecules. Stable peptide–MHC-I complexes are presented at the cell surface to mirror cellular contents for patrolling T cells, which protect against viral infections and cancer-causing mutations by inducing apoptosis in cells that expose nonself peptides. Due to its size and dynamic nature, the atomic-level details of the PLC remained unknown. We built an all-atom model of the human MHC-I PLC by combining the recent 9.9-Å resolution cryo-EM density with microsecond molecular dynamics simulations in a membrane and water environment (1.6 million atoms). The results provide unprecedented insights into the molecular underpinnings of our adaptive immune response.