4TXZ

Crystal structure of Vibrio cholerae DncV cyclic AMP-GMP synthase in complex with nonhydrolyzable GTP

Summary for 4TXZ

• Entry DOI: 10.2210/pdb4txz/pdb
• Descriptor: Cyclic AMP-GMP synthase, MAGNESIUM ION, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, ... (4 entities in total)
• Functional Keywords: nucleotidyl transferase, cyclic nucleotide synthase, cgas, transferase
• Biological source: Vibrio cholerae O1 biovar El Tor str. N16961
• Total number of polymer chains: 2
• Total formula weight: 95072.26

Authors

Kranzusch, P.J.,Lee, A.S.Y.,Wilson, S.C.,Solovykh, M.S.,Vance, R.E.,Berger, J.M.,Doudna, J.A. (deposition date: 2014-07-07, release date: 2014-08-13, Last modification date: 2023-12-27)

Primary citation

Kranzusch, P.J.,Lee, A.S.,Wilson, S.C.,Solovykh, M.S.,Vance, R.E.,Berger, J.M.,Doudna, J.A.
Structure-Guided Reprogramming of Human cGAS Dinucleotide Linkage Specificity.
Cell, 158:1011-1021, 2014

PubMed Abstract: Cyclic dinucleotides (CDNs) play central roles in bacterial pathogenesis and innate immunity. The mammalian enzyme cGAS synthesizes a unique cyclic dinucleotide (cGAMP) containing a 2'-5' phosphodiester linkage essential for optimal immune stimulation, but the molecular basis for linkage specificity is unknown. Here, we show that the Vibrio cholerae pathogenicity factor DncV is a prokaryotic cGAS-like enzyme whose activity provides a mechanistic rationale for the unique ability of cGAS to produce 2'-5' cGAMP. Three high-resolution crystal structures show that DncV and human cGAS generate CDNs in sequential reactions that proceed in opposing directions. We explain 2' and 3' linkage specificity and test this model by reprogramming the human cGAS active site to produce 3'-5' cGAMP, leading to selective stimulation of alternative STING adaptor alleles in cells. These results demonstrate mechanistic homology between bacterial signaling and mammalian innate immunity and explain how active site configuration controls linkage chemistry for pathway-specific signaling.

PubMed: 25131990
DOI: 10.1016/j.cell.2014.07.028

Experimental method

X-RAY DIFFRACTION (2.8 Å)