Adaptive immunity depends on major histocompatibility complex class I (MHC I) presentation of peptides, a process orchestrated by the peptide-loading complex (PLC) in the endoplasmic reticulum. The PLC ensures precise peptide selection and loading and is a major target of viral immune evasion, notably by human cytomegalovirus (HCMV). Here, we report the 2.59–2.88 Å cryo-electron microscopy structure of native human PLC bound to the HCMV immune evasin US6. US6 inhibits the TAP1/2 transporter by laterally attaching its transmembrane helix to TAP2 using a disulfide-rich domain to mimic a translocating peptide. This domain blocks the ER-lumenal exit and locks TAP in an outward-facing conformation with closed nucleotide-binding domains and asymmetric ATP/ADP occlusion. The structure also reveals how TAP’s N-terminal transmembrane domains scaffold the MHC I chaperone tapasin. These findings elucidate the mechanism of US6-mediated immune evasion and highlight potential targets for therapeutic modulation of immune presentation in infection and cancer.

Raw Data Source Data File (after revision and acceptance of manuscript)
Figure 4d and 4g
SI fig. S1a, b, d, e
SI fig. S8d, e