Scientists have developed a structure-guided computational procedure that searches large databases of phage genomes and predicts phage proteins that manipulate bacterial immune signaling.[1] This procedure identified three new families of previously unknown proteins: Sequestin and Lockin, which bind and sequester the signaling molecules 3′cADPR and His-ADPR produced by the TIR system, and Acb5, which cleaves and inactivates 3′3′-cGAMP and related molecules.[1] These proteins inhibit the bacterial Thoeris and CBASS systems.[1] X-ray crystallography, structural modeling, and mutational analyzes have elucidated the structural basis of the sequestration or cleavage of immunological signals.[1] Thousands of such signal-handling proteins have been detected in phage protein databases, including instances in the well-studied phages T2, T4, and T6.[1] The study describes three new families of anti-defense proteins targeting host immune signaling, represented in more than 5000 proteins in the phage protein data.[1] Biochemical and structural analyzes characterized their interactions with target molecules.[1]