9vyl
Crystal structure of BdThsB1 with NAD
Structural highlights
FunctionTHSB1_CYTDA One of 2 TIR-like protein components of the Thoeris antiviral defense system, composed of ThsA, TIR1 (thsB1) and TIR2 (thsB2). Phage infection activates this protein; by 70 minutes post-infection with phage SPO1, TIR1 generates a signal molecule that activates the NAD(+) hydrolase activity of ThsA (tested with B.cereus). The signal is similar to cyclic ADP-D-ribose, but how it differs is unknown. Expression of Thoeris in B.subtilis (strain BEST7003) confers resistance to phages phi29, phi3T, SPBeta, SBSphi11, SBSphi13, SBSphiJ, SPO1 and SPR but not SBSphiC. The TIR paralogs confer resistance to different phages; this subunit confers resistance to phi29, SBSphi11, SBSphi13, SBSphiJ, SPO1 and SPR but not phi3T, SBSphiC or SPBeta. There is overlap in the phage range for this system, both TIR1 and TIR2 are activated by SBSphi13, SBSphiJ, SPO1 and SPR. Probably hydrolyzes NAD(+) to make a cyclic ADP-D-ribose (cADPR) signaling molecule; might make 3'cADPR (By similarity).[UniProtKB:J8CSK2][1] Publication Abstract from PubMedThe Type 1 Thoeris defense system is an NAD(+)-based innate immune mechanism that protects bacterial populations against viral infection by triggering NAD(+) depletion-induced cell death. Central to this system is the TIR domain-containing protein Ths B, which uses NAD(+) to synthesize a cyclic ADPR (cADPR) signal upon sensing viral antigens. However, the structural basis of NAD(+) binding by Ths B remains poorly understood. Here, we report the 1.54 A resolution X-ray crystal structure of the Thoeris B1 protein from Bacillus dafuensis (Bd) in complex with NAD(+). The structure reveals a canonical TIR fold comprising a five-stranded parallel beta-sheet flanked by five alpha-helices, along with an unpredicted CCCH-type zinc finger domain formed by two flexible loops and a hydrophobic cavity. NAD(+) binds in a distinctive C-shaped conformation, engaging residues near the conserved catalytic core. These findings suggest a pre-activation binding of NAD(+) prior to antigen detection, providing structural clues into the specificity and catalytic mechanism of cADPR production. Our study uncovers unique structural features of bacterial TIR domains and expands our understanding of the molecular basis of Thoeris-mediated antiviral immunity. Crystal structure of Bacillus dafuensis Thoeris B1 protein in complex with NAD().,Hong S, Choe J Biochem Biophys Res Commun. 2025 Dec 31;793:153001. doi: , 10.1016/j.bbrc.2025.153001. Epub 2025 Nov 19. PMID:41270486[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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