7d4j
ddATP complex of cyclic trinucleotide synthase CdnDddATP complex of cyclic trinucleotide synthase CdnD
Structural highlights
FunctionCDND2_ENTCL CBASS (cyclic oligonucleotide-based antiphage signaling system) provides immunity against bacteriophage. The CD-NTase protein synthesizes cyclic nucleotides in response to infection; these serve as specific second messenger signals. The signals activate a diverse range of effectors, leading to bacterial cell death and thus abortive phage infection. A type II-C(AAG) CBASS system (PubMed:32839535).[1] [2] Cyclic trinucleotide synthase that catalyzes the synthesis of 3',3',3'-cyclic AMP-AMP-GMP as the major product, a second messenger for cell signal transduction.[3] Protects E.coli against phage T2 infection. When the cdnD-cap2-cap3-cap4 operon is introduced in E.coli there is a more than 10(3) decrease in the efficiency of T2 plaque formation. The operon does not protect against phage T5 and only about 10-fold against T7.[4] Publication Abstract from PubMedMammalian cyclic GMP-AMP synthase (cGAS) and its homologue dinucleotide cyclase in Vibrio cholerae (VcDncV) produce cyclic dinucleotides (CDNs) that participate in the defense against viral infection. Recently, scores of new cGAS/DncV-like nucleotidyltransferases (CD-NTases) were discovered, which produce various CDNs and cyclic trinucleotides (CTNs) as second messengers. Here, we present the crystal structures of EcCdnD, a CD-NTase from Enterobacter cloacae that produces cyclic AMP-AMP-GMP, in its apo-form and in complex with ATP, ADP and AMPcPP, an ATP analogue. Despite the similar overall architecture, the protein shows significant structural variations from other CD-NTases. Adjacent to the donor substrate, another nucleotide is bound to the acceptor binding site by a non-productive mode. Isothermal titration calorimetry results also suggest the presence of two ATP binding sites. GTP alone does not bind to EcCdnD, which however binds to pppApG, a possible intermediate. The enzyme is active on ATP or a mixture of ATP and GTP, and the best metal cofactor is Mg2+. The conserved residues Asp69 and Asp71 are essential for catalysis, as indicated by the loss of activity in the mutants. Based on structural analysis and comparison with VcDncV and RNA polymerase, a tentative catalytic pathway for the CTN-producing EcCdnD is proposed. Crystal structure and functional implication of a bacterial cyclic AMP-AMP-GMP synthetase.,Ko TP, Wang YC, Tsai CL, Yang CS, Hou MH, Chen Y Nucleic Acids Res. 2021 Apr 9. pii: 6219115. doi: 10.1093/nar/gkab165. PMID:33836064[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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