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| | <StructureSection load='5xzb' size='340' side='right'caption='[[5xzb]], [[Resolution|resolution]] 2.13Å' scene=''> | | <StructureSection load='5xzb' size='340' side='right'caption='[[5xzb]], [[Resolution|resolution]] 2.13Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5xzb]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XZB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XZB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5xzb]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XZB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XZB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A9Y:(3R)-3-[1-(1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]-2-benzofuran-1(3H)-one'>A9Y</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.13Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Mb21d1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A9Y:(3R)-3-[1-(1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]-2-benzofuran-1(3H)-one'>A9Y</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclic_GMP-AMP_synthase Cyclic GMP-AMP synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.86 2.7.7.86] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5xzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xzb OCA], [https://pdbe.org/5xzb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xzb RCSB], [https://www.ebi.ac.uk/pdbsum/5xzb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xzb ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5xzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xzb OCA], [http://pdbe.org/5xzb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xzb RCSB], [http://www.ebi.ac.uk/pdbsum/5xzb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xzb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CGAS_MOUSE 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. | + | [https://www.uniprot.org/uniprot/CGAS_MOUSE 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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cyclic GMP-AMP synthase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Adura, C]] | + | [[Category: Adura C]] |
| - | [[Category: Aida, J]] | + | [[Category: Aida J]] |
| - | [[Category: Asano, Y]] | + | [[Category: Asano Y]] |
| - | [[Category: Ascano, M]] | + | [[Category: Ascano M]] |
| - | [[Category: Aso, K]] | + | [[Category: Aso K]] |
| - | [[Category: Gao, P]] | + | [[Category: Gao P]] |
| - | [[Category: Glickman, J F]] | + | [[Category: Glickman JF]] |
| - | [[Category: Gogakos, T]] | + | [[Category: Gogakos T]] |
| - | [[Category: Imaeda, T]] | + | [[Category: Imaeda T]] |
| - | [[Category: Lama, L]] | + | [[Category: Lama L]] |
| - | [[Category: Luz, A]] | + | [[Category: Luz A]] |
| - | [[Category: Okamoto, R]] | + | [[Category: Okamoto R]] |
| - | [[Category: Patel, D J]] | + | [[Category: Patel DJ]] |
| - | [[Category: Reasoner, S]] | + | [[Category: Reasoner S]] |
| - | [[Category: Rothamel, K]] | + | [[Category: Rothamel K]] |
| - | [[Category: Steinberg, J]] | + | [[Category: Steinberg J]] |
| - | [[Category: Tuschl, T]] | + | [[Category: Tuschl T]] |
| - | [[Category: Vincent, J]] | + | [[Category: Vincent J]] |
| - | [[Category: Cga]]
| + | |
| - | [[Category: Immune system-inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Sting]]
| + | |
| Structural highlights
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
Cyclic GMP-AMP synthase is essential for innate immunity against infection and cellular damage, serving as a sensor of DNA from pathogens or mislocalized self-DNA. Upon binding double-stranded DNA, cyclic GMP-AMP synthase synthesizes a cyclic dinucleotide that initiates an inflammatory cellular response. Mouse studies that recapitulate causative mutations in the autoimmune disease Aicardi-Goutieres syndrome demonstrate that ablating the cyclic GMP-AMP synthase gene abolishes the deleterious phenotype. Here, we report the discovery of a class of cyclic GMP-AMP synthase inhibitors identified by a high-throughput screen. These compounds possess defined structure-activity relationships and we present crystal structures of cyclic GMP-AMP synthase, double-stranded DNA, and inhibitors within the enzymatic active site. We find that a chemically improved member, RU.521, is active and selective in cellular assays of cyclic GMP-AMP synthase-mediated signaling and reduces constitutive expression of interferon in macrophages from a mouse model of Aicardi-Goutieres syndrome. RU.521 will be useful toward understanding the biological roles of cyclic GMP-AMP synthase and can serve as a molecular scaffold for development of future autoimmune therapies.Upon DNA binding cyclic GMP-AMP synthase (cGAS) produces a cyclic dinucleotide, which leads to the upregulation of inflammatory genes. Here the authors develop small molecule cGAS inhibitors, functionally characterize them and present the inhibitor and DNA bound cGAS crystal structures, which will facilitate drug development.
Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice.,Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K, Gogakos T, Steinberg J, Reasoner S, Aso K, Tuschl T, Patel DJ, Glickman JF, Ascano M Nat Commun. 2017 Sep 29;8(1):750. doi: 10.1038/s41467-017-00833-9. PMID:28963528[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K, Gogakos T, Steinberg J, Reasoner S, Aso K, Tuschl T, Patel DJ, Glickman JF, Ascano M. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun. 2017 Sep 29;8(1):750. doi: 10.1038/s41467-017-00833-9. PMID:28963528 doi:http://dx.doi.org/10.1038/s41467-017-00833-9
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