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Literature summary for 2.7.7.86 extracted from

  • Zhao, W.; Xiong, M.; Yuan, X.; Li, M.; Sun, H.; Xu, Y.
    In silico screening-based discovery of novel inhibitors of human cyclic GMP-AMP synthase a cross-validation study of molecular docking and experimental testing (2020), J. Chem. Inf. Model., 60, 3265-3276 .
    View publication on PubMed

Cloned(Commentary)

Cloned (Comment) Organism
gene CGAS, recombinant expression of isolated His-tagged h-cGAS catalytic domain in Escherichia coli strain Rosetta 2(DE3) Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
purified recombinant h-cGASCD in apoform and complexed with inhibitors, by hanging drop vapor diffusion method, mixing of 0.0015 ml of 8-9 mg/ml protein in 20 mM HEPES, pH 7.5, 250 mM KCl, 1 mM TCEP, and 10% glycerine, with 0.0015 ml of reservoir solution containing 17.5-19% v/v PEG 3350 and 0.2 M ammonium citrate, pH 7.0-7.5, 4°C, soaking of crystals for the inhibitor PF-06928215-enzyme complex, X-ray diffraction structure determination and analysis at 1.8 A resolution, molecular replacement using structure PDB ID 4LEV as a search model Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(1R,2S)-2-(7-oxo-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexane-1-carboxylic acid PF-06928215, a commercial inhibitor, enzyme binding structure analysis, the pyrazolopyrimidine of PF-06928215 is sandwiched between the guanidinium group of R376 and the aromatic ring of Y436, mimicking the nucleobase. The benzene is anchored in a hydrophobic subpocket lined by the side chains of F488 and L490, molecular dynamics simulations, overview Homo sapiens
(3R)-1-(pyrrolo[1,2-a]quinoxalin-4-yl)piperidine-3-carboxylic acid 16.8% inhibition at 0.1 mM Homo sapiens
1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline-6,7-dicarboxylic acid 39.9% inhibition at 0.1 mM Homo sapiens
1-[9-(6-aminopyridin-3-yl)-6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethan-1-one
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Homo sapiens
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one RU-521 or RU.521 Homo sapiens
3-[5-(carboxymethyl)-3-oxo-3,5-dihydro[1,2,4]triazino[2,3-a]benzimidazol-2-yl]propanoic acid 29.9% inhibition at 0.1 mM Homo sapiens
4-[2-(2-methyl[1,2,4]triazolo[1,5-c]quinazolin-5-yl)hydrazinyl]-4-oxobutanoic acid 21.8% inhibition at 0.1 mM Homo sapiens
7-methoxy-N9-methyl-N9-[3-[methyl(pyridin-4-yl)amino]propyl]acridine-3,9-diamine
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Homo sapiens
additional information in silico screening-based discovery of inhibitors of human cyclic GMP-AMP synthase, cross-validation study of molecular docking and experimental testing, usage of catalytic domain of human cGAS (h-cGASCD) for virtual screening, overview Homo sapiens
suramin
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Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + GTP Homo sapiens overall reaction 2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
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?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q8N884
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-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged catalytic domain of h-cGAS from Escherichia coli strain Rosetta 2(DE3) by nickel affinity chromatography, dialysis, heparin ion exchange chromatography, and gel filtration Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + GTP overall reaction Homo sapiens 2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
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?
additional information a diphosphatase-coupled cGAS activity assay is performed Homo sapiens ?
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-

Synonyms

Synonyms Comment Organism
cGAS
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Homo sapiens
h-cGAS
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Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
22
-
assay at room temperature Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.5
-
assay at Homo sapiens

General Information

General Information Comment Organism
additional information molecular dynamics simulations and structure modeling, overview Homo sapiens