biostudies-literatureStolz MEuropean Research Councileaea7735https://www.ebi.ac.uk/biostudies/studies/S-EPMC12758552biostudies-literatureUnknown12(1)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 (ER). 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- to 2.88-Å cryo-electron microscopy structure of native human PLC bound to the HCMV immune evasin US6. US6 inhibits the transporter associated with antigen processing 1/2 (TAP1/2) 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 asymmScience advancesArchitectural principles of transporter-chaperone coupling within the native MHC I peptide-loading complex.PMC12758552101141396Susac LTampe RKeller RSaggau LFahim AMancia FTrowitzsch SStolz MfalseArchitectural principles of transporter-chaperone coupling within the native MHC I peptide-loading complex.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 (ER). 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- to 2.88-Å cryo-electron microscopy structure of native human PLC bound to the HCMV immune evasin US6. US6 inhibits the transporter associated with antigen processing 1/2 (TAP1/2) 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 asymm2026-01-01T00:00:00Z2026 Jan2026-06-09T05:15:46.02Z2026-06-09T03:07:29.488ZS-EPMC127585524148173310.1126/sciadv.aea7735