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bioRxiv · 10.1101/2025.06.19.660632

A Structural Atlas of TAP Inhibition by Herpesviruses and Poxviruses

Lee, J.·Manon, V.·Chen, J.
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Abstract

In the host-pathogen arms race, herpesviruses and poxviruses encode proteins that sabotage the transporter associated with antigen processing (TAP), thereby suppressing MHC-I antigen presentation and enabling lifelong infection. Of the five known viral TAP inhibitors, only the herpes simplex virus protein ICP47 has been structurally resolved. We now report cryo-electron microscopy structures of TAP in complex with the remaining four: BNLF2a (Epstein-Barr virus), hUS6 (human cytomegalovirus), bUL49.5 (bovine herpesvirus 1), and CPXV012 (cowpox virus), assembling a structural atlas of viral TAP evasion. Employing divergent sequences, folds and conformational targets, these viral inhibitors converge on a common strategy: they stall TAP from the alternating access cycle, precluding peptide entry into the ER and shielding infected cells from cytotoxic T-cell surveillance. These findings reveal striking functional convergence and provide a structural framework for rational antiviral design.

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Lee, J., Manon, V., Chen, J.. 2025-06-20. A Structural Atlas of TAP Inhibition by Herpesviruses and Poxviruses. https://doi.org/10.1101/2025.06.19.660632

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