Structural basis for broad anti-phage immunity by DISARM Bravo, Jack Peter Kelly ; https://orcid.org/0000-0003-0456-0753 Aparicio-Maldonado, Cristian Nobrega, Franklin L. Brouns, Stan J. J. Taylor, David W. General Physics and Astronomy General Biochemistry Genetics and Molecular Biology General Chemistry Multidisciplinary In the evolutionary arms race against phage, bacteria have assembled a diverse arsenal of antiviral immune strategies. While the recently discovered DISARM (Defense Island System Associated with Restriction-Modification) systems can provide protection against a wide range of phage, the molecular mechanisms that underpin broad antiviral targeting but avoiding autoimmunity remain enigmatic. Here, we report cryo-EM structures of the core DISARM complex, DrmAB, both alone and in complex with an unmethylated phage DNA mimetic. These structures reveal that DrmAB core complex is autoinhibited by a trigger loop (TL) within DrmA and binding to DNA substrates containing a 5′ overhang dislodges the TL, initiating a long-range structural rearrangement for DrmAB activation. Together with structure-guided in vivo studies, our work provides insights into the mechanism of phage DNA recognition and specific activation of this widespread antiviral defense system. Springer Nature 2022 info:eu-repo/semantics/article doc-type:article text http://purl.org/coar/resource_type/c_2df8fbb1 https://research-explorer.ista.ac.at/record/15133 Bravo JPK, Aparicio-Maldonado C, Nobrega FL, Brouns SJJ, Taylor DW. Structural basis for broad anti-phage immunity by DISARM. <i>Nature Communications</i>. 2022;13. doi:<a href="https://doi.org/10.1038/s41467-022-30673-1">10.1038/s41467-022-30673-1</a> eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-022-30673-1 info:eu-repo/semantics/altIdentifier/issn/2041-1723 info:eu-repo/semantics/altIdentifier/pmid/35624106 info:eu-repo/semantics/openAccess