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ZAP has no intrinsic catalytic activity but inhibits viral replication by binding to CpG dinucleotides in cytoplasmic viral RNA and recruiting other factors to inhibit protein synthesis and target the RNA for degradation. KHNYN is a ZAP-binding protein required for ZAP-restriction of CpG-rich viral genomes. It contains an extended diKH, PIN nuclease, and CUElike domain, each of which are required for ZAP restriction of viral replication. Here, we report a structural, enzymological, and virological study of KHNYN\u2019s essential PIN nuclease domain. Our crystal structure reveals an extended PIN domain (ex-PIN) containing a conserved N-terminal arm region required for domain stability and an active site tetra-Asp motif, which are both required for antiviral activity. Unlike the weak activity recently reported for the PIN domain, we demonstrate that the KHNYN ex-PIN domain is a highly active Mn2+-dependent single-stranded RNA endonuclease that cleaves with a preference for ApC, ApA, and UpA dinucleotides. These observations extend our view of KHNYN antiviral activity and suggest an unforeseen role for activation by manganese ions in the ZAP\u2013KHNYN antiviral response.<\/jats:p>","DOI":"10.1093\/nar\/gkaf1360","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:53:18Z","timestamp":1763470398000},"source":"Crossref","is-referenced-by-count":2,"title":["KHNYN is a manganese-dependent endoribonuclease required for ZAP-mediated antiviral restriction"],"prefix":"10.1093","volume":"53","author":[{"given":"Rebecca L","family":"Youle","sequence":"first","affiliation":[{"name":"The Francis Crick Institute, Macromolecular Structure Laboratory , 1 Midland Road, London NW1 1AT ,","place":["UK"]},{"name":"King\u2019s College London, Department of Infectious Diseases, Floor 2 Borough Wing Guy\u2019s Hospital , London SE1 9RT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Jose","family":"Lista","sequence":"additional","affiliation":[{"name":"King\u2019s College London, Department of Infectious Diseases, Floor 2 Borough Wing Guy\u2019s Hospital , London SE1 9RT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma L","family":"Brudenell","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, Macromolecular Structure Laboratory , 1 Midland Road, London NW1 1AT ,","place":["UK"]},{"name":"AstraZeneca, The Discovery Centre , 1 Francis Crick Avenue, Cambridge CB2 0AA ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley","family":"Thompson","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, Macromolecular Structure Laboratory , 1 Midland Road, London NW1 1AT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clement","family":"Bouton","sequence":"additional","affiliation":[{"name":"King\u2019s College London, Department of Infectious Diseases, Floor 2 Borough Wing Guy\u2019s Hospital , London SE1 9RT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth R","family":"Morris","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, Macromolecular Structure Laboratory , 1 Midland Road, London NW1 1AT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart J D","family":"Neil","sequence":"additional","affiliation":[{"name":"King\u2019s College London, Department of Infectious Diseases, Floor 2 Borough Wing Guy\u2019s Hospital , London SE1 9RT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chad M","family":"Swanson","sequence":"additional","affiliation":[{"name":"King\u2019s College London, Department of Infectious Diseases, Floor 2 Borough Wing Guy\u2019s Hospital , London SE1 9RT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6763-3852","authenticated-orcid":false,"given":"Ian A","family":"Taylor","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, Macromolecular Structure Laboratory , 1 Midland Road, London NW1 1AT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"2025121705163812600_B1","doi-asserted-by":"publisher","first-page":"e1009545","DOI":"10.1371\/journal.ppat.1009545","article-title":"Origin and evolution of the zinc finger antiviral protein","volume":"17","author":"Goncalves-Carneiro","year":"2021","journal-title":"PLoS Pathog"},{"key":"2025121705163812600_B2","doi-asserted-by":"publisher","first-page":"e2004086","DOI":"10.1371\/journal.pbio.2004086","article-title":"Fundamental properties of the mammalian innate immune system revealed by multispecies 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