9RCV

Structure of the Human Peptide-Loading Complex Arrested by HCMV US6

Summary for 9RCV

• Entry DOI: 10.2210/pdb9rcv/pdb
• EMDB information: 53923
• Descriptor: Antigen peptide transporter 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ADENOSINE-5'-DIPHOSPHATE, ... (12 entities in total)
• Functional Keywords: antigen processing, adaptive immunity, cryo-em, er chaperones, mhc class i, transporter associated with antigen processing, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 382497.08

Authors

Stolz, M.,Susac, L.,Trowitzsch, S.,Tampe, R. (deposition date: 2025-05-29, release date: 2025-12-03, Last modification date: 2026-02-11)

Primary citation

Stolz, M.,Susac, L.,Fahim, A.,Keller, R.,Saggau, L.,Mancia, F.,Trowitzsch, S.,Tampe, R.
Architectural principles of transporter-chaperone coupling within the native MHC I peptide-loading complex.
Sci Adv, 12:eaea7735-eaea7735, 2026

PubMed Abstract: 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 asymmetric adenosine 5'-triphosphate/adenosine 5'-diphosphate occlusion. The structure also reveals how TAP's amino-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.

PubMed: 41481733
DOI: 10.1126/sciadv.aea7735

Experimental method

ELECTRON MICROSCOPY (2.7 Å)