7buq

mcGAS bound with 23-cGAMP

spinqualitylabelsall models 7buq, resolution 3.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7buq is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.091Å Ligands: 1SY, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CGAS_MOUSE 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 DNA binding allosterically activates the cytosolic DNA sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2'3'-cGAMP, using Mg(2+) as the metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found that Mn(2+) potentiates cGAS activation, but the underlying mechanism remains unclear. Here, we report that Mn(2+) directly activates cGAS. Structural analysis reveals that Mn(2+)-activated cGAS undergoes globally similar conformational changes to DNA-activated cGAS but forms a unique eta1 helix to widen the catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in Mn(2+)-activated cGAS, the linear intermediates pppGpG and pGpA take an inverted orientation in the active pocket, suggesting a noncanonical but accelerated cGAMP cyclization without substrate flip-over. Moreover, unlike the octahedral coordination around Mg(2+), the two catalytic Mn(2+) are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Our findings thus uncover Mn(2+) as a cGAS activator that initiates noncanonical 2'3'-cGAMP synthesis. Mn(2+) Directly Activates cGAS and Structural Analysis Suggests Mn(2+) Induces a Noncanonical Catalytic Synthesis of 2'3'-cGAMP.,Zhao Z, Ma Z, Wang B, Guan Y, Su XD, Jiang Z Cell Rep. 2020 Aug 18;32(7):108053. doi: 10.1016/j.celrep.2020.108053. PMID:32814054 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cyclic GMP-AMP synthase 3D synthase

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