4K9A

Structure of Ternary Complex of cGAS with dsDNA and Bound 5 -pG(2 ,5 )pA

Summary for 4K9A

• Entry DOI: 10.2210/pdb4k9a/pdb
• Descriptor: Cyclic GMP-AMP synthase, DNA-F, DNA-R, ... (8 entities in total)
• Functional Keywords: nucleotidyltransferase fold, transferase-dna complex, transferase/dna
• Biological source: Mus musculus (mouse); More
• Cellular location: Cytoplasm, cytosol: Q8C6L5
• Total number of polymer chains: 3
• Total formula weight: 53795.74

Authors

Gao, P.,Wu, Y.,Patel, D.J. (deposition date: 2013-04-19, release date: 2013-05-15, Last modification date: 2024-05-29)

Primary citation

Gao, P.,Ascano, M.,Wu, Y.,Barchet, W.,Gaffney, B.L.,Zillinger, T.,Serganov, A.A.,Liu, Y.,Jones, R.A.,Hartmann, G.,Tuschl, T.,Patel, D.J.
Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase.
Cell(Cambridge,Mass.), 153:1094-1107, 2013

PubMed Abstract: Recent studies identified cyclic GMP-AMP (cGAMP) as a metazoan second messenger triggering an interferon response. cGAMP is generated from GTP and ATP by cytoplasmic dsDNA sensor cGAMP synthase (cGAS). We combined structural, chemical, biochemical, and cellular assays to demonstrate that this second messenger contains G(2',5')pA and A(3',5')pG phosphodiester linkages, designated c[G(2',5')pA(3',5')p]. We show that, upon dsDNA binding, cGAS is activated through conformational transitions, resulting in formation of a catalytically competent and accessible nucleotide-binding pocket for generation of c[G(2',5')pA(3',5')p]. We demonstrate that cyclization occurs in a stepwise manner through initial generation of 5'-pppG(2',5')pA prior to cyclization to c[G(2',5')pA(3',5')p], with the latter positioned precisely in the catalytic pocket. Mutants of cGAS dsDNA-binding or catalytic pocket residues exhibit reduced or abrogated activity. Our studies have identified c[G(2',5')pA(3',5')p] as a founding member of a family of metazoan 2',5'-containing cyclic heterodinucleotide second messengers distinct from bacterial 3',5' cyclic dinucleotides.

PubMed: 23647843
DOI: 10.1016/j.cell.2013.04.046

Experimental method

X-RAY DIFFRACTION (2.264 Å)