5vdo | pdb_00005vdo

Human cyclic GMP-AMP synthase (cGAS) in complex with 2',2'-cGAMP

spinqualitylabelsall models 5vdo, resolution 3.22Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5vdo is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1YC, ZN Related: 5vdp, 5vdq, 5vdr, 5vds, 5vdt, 5vdu, 5vdv, 5vdw Gene: MB21D1, C6orf150 (HUMAN) Activity: Cyclic GMP-AMP synthase, with EC number 2.7.7.86 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CGAS_HUMAN] Nucleotidyltransferase that catalyzes formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and exhibits antiviral activity. Has antiviral activity by acting as a key cytosolic DNA sensor, the presence of DNA in the cytoplasm being a danger signal that triggers the immune responses. Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production. Publication Abstract from PubMed Cyclic GMP-AMP synthase (cGAS) is activated by ds-DNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds-DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2',3'-cGAMP formation, and interestingly, describe a catalytic mechanism where 2',3'-cGAMP may be a minor product of cGAS compared to linear nucleotides. This article is protected by copyright. All rights reserved. The catalytic mechanism of cyclic gmp-amp synthase (cGAS) and implications for innate immunity and inhibition.,Hall J, Ralph EC, Shanker S, Wang H, Byrnes LJ, Horst R, Wong J, Brault A, Dumlao D, Smith JF, Dakin LA, Schmitt DC, Trujillo J, Vincent F, Griffor M, Aulabaugh AE Protein Sci. 2017 Sep 22. doi: 10.1002/pro.3304. PMID:28940468 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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