InChI=1S/C30H36N15O18P3/c31-22-13-25(37-4-34-22)43(7-40-13)28-16(46)19-10(58-28)1-55-64(49,50)62-20-11(59-29(17(20)47)44-8-41-14-23(32)35-5-38-26(14)44)2-57-66(53,54)63-21-12(3-56-65(51,52)61-19)60-30(18(21)48)45-9-42-15-24(33)36-6-39-27(15)45/h4-12,16-21,28-30,46-48H,1-3H2,(H,49,50)(H,51,52)(H,53,54)(H2,31,34,37)(H2,32,35,38)(H2,33,36,39)/p-3/t10-,11-,12-,16-,17-,18-,19-,20-,21-,28-,29-,30-/m1/s1 |
OEJXFVYXZQYNND-UQTMIEBXSA-K |
[C@@H]1(N2C3=C(C(N)=NC=N3)N=C2)O[C@H]4[C@H]([C@H]1O)OP(=O)([O-])OC[C@H]5O[C@@H](N6C7=C(C(N)=NC=N7)N=C6)[C@@H]([C@@H]5OP([O-])(=O)OC[C@H]8O[C@@H](N9C%10=C(C(N)=NC=N%10)N=C9)[C@@H]([C@@H]8OP(OC4)(=O)[O-])O)O |
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3',3',3'-c-tri-AMP
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SUBMITTER
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3',3',3'-c-tri-AMP
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UniProt
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3'3'3'-cAAA
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SUBMITTER
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3'3'3'-cyclic AMP-AMP-AMP
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SUBMITTER
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Hobbs SJ, Wein T, Lu A, Morehouse BR, Schnabel J, Leavitt A, Yirmiya E, Sorek R, Kranzusch PJ (2022) Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity. Nature 605, 522-526 (Source: SUBMITTER) [PubMed:35395152] [show Abstract] The cyclic oligonucleotide-based antiphage signalling system (CBASS) and the pyrimidine cyclase system for antiphage resistance (Pycsar) are antiphage defence systems in diverse bacteria that use cyclic nucleotide signals to induce cell death and prevent viral propagation1,2. Phages use several strategies to defeat host CRISPR and restriction-modification systems3-10, but no mechanisms are known to evade CBASS and Pycsar immunity. Here we show that phages encode anti-CBASS (Acb) and anti-Pycsar (Apyc) proteins that counteract defence by specifically degrading cyclic nucleotide signals that activate host immunity. Using a biochemical screen of 57 phages in Escherichia coli and Bacillus subtilis, we discover Acb1 from phage T4 and Apyc1 from phage SBSphiJ as founding members of distinct families of immune evasion proteins. Crystal structures of Acb1 in complex with 3'3'-cyclic GMP-AMP define a mechanism of metal-independent hydrolysis 3' of adenosine bases, enabling broad recognition and degradation of cyclic dinucleotide and trinucleotide CBASS signals. Structures of Apyc1 reveal a metal-dependent cyclic NMP phosphodiesterase that uses relaxed specificity to target Pycsar cyclic pyrimidine mononucleotide signals. We show that Acb1 and Apyc1 block downstream effector activation and protect from CBASS and Pycsar defence in vivo. Active Acb1 and Apyc1 enzymes are conserved in phylogenetically diverse phages, demonstrating that cleavage of host cyclic nucleotide signals is a key strategy of immune evasion in phage biology. | Ye Q, Lau RK, Mathews IT, Birkholz EA, Watrous JD, Azimi CS, Pogliano J, Jain M, Corbett KD (2020) HORMA Domain Proteins and a Trip13-like ATPase Regulate Bacterial cGAS-like Enzymes to Mediate Bacteriophage Immunity. Molecular cell 77, 709-722.e7 (Source: SUBMITTER) [PubMed:31932165] [show Abstract] Bacteria are continually challenged by foreign invaders, including bacteriophages, and have evolved a variety of defenses against these invaders. Here, we describe the structural and biochemical mechanisms of a bacteriophage immunity pathway found in a broad array of bacteria, including E. coli and Pseudomonas aeruginosa. This pathway uses eukaryotic-like HORMA domain proteins that recognize specific peptides, then bind and activate a cGAS/DncV-like nucleotidyltransferase (CD-NTase) to generate a cyclic triadenylate (cAAA) second messenger; cAAA in turn activates an endonuclease effector, NucC. Signaling is attenuated by a homolog of the AAA+ ATPase Pch2/TRIP13, which binds and disassembles the active HORMA-CD-NTase complex. When expressed in non-pathogenic E. coli, this pathway confers immunity against bacteriophage λ through an abortive infection mechanism. Our findings reveal the molecular mechanisms of a bacterial defense pathway integrating a cGAS-like nucleotidyltransferase with HORMA domain proteins for threat sensing through protein detection and negative regulation by a Trip13 ATPase. |
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