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| | <StructureSection load='6o47' size='340' side='right'caption='[[6o47]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='6o47' size='340' side='right'caption='[[6o47]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6o47]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O47 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O47 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6o47]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O47 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O47 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AEV:2-(4,5-dichloro-1H-benzimidazol-2-yl)-5-methyl-4-[(1R)-3-oxo-1,3-dihydro-2-benzofuran-1-yl]-1,2-dihydro-3H-pyrazol-3-one'>AEV</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=LLS:(3~{S})-3-[1-[4,5-bis(chloranyl)-1~{H}-benzimidazol-2-yl]-3-methyl-5-oxidanyl-pyrazol-4-yl]-3~{H}-2-benzofuran-1-one'>LLS</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]] 2.196Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CGAS, C6orf150, MB21D1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AEV:2-(4,5-dichloro-1H-benzimidazol-2-yl)-5-methyl-4-[(1R)-3-oxo-1,3-dihydro-2-benzofuran-1-yl]-1,2-dihydro-3H-pyrazol-3-one'>AEV</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=LLS:(3~{S})-3-[1-[4,5-bis(chloranyl)-1~{H}-benzimidazol-2-yl]-3-methyl-5-oxidanyl-pyrazol-4-yl]-3~{H}-2-benzofuran-1-one'>LLS</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=6o47 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o47 OCA], [https://pdbe.org/6o47 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o47 RCSB], [https://www.ebi.ac.uk/pdbsum/6o47 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o47 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=6o47 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o47 OCA], [http://pdbe.org/6o47 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o47 RCSB], [http://www.ebi.ac.uk/pdbsum/6o47 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o47 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CGAS_HUMAN 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.<ref>PMID:21478870</ref> <ref>PMID:23258413</ref> | + | [https://www.uniprot.org/uniprot/CGAS_HUMAN 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.<ref>PMID:21478870</ref> <ref>PMID:23258413</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6o47" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6o47" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cyclic GMP-AMP synthase 3D synthase|Cyclic GMP-AMP synthase 3D synthase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cyclic GMP-AMP synthase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Adura, C]] | + | [[Category: Adura C]] |
| - | [[Category: Glickman, J F]] | + | [[Category: Glickman JF]] |
| - | [[Category: Lama, L]] | + | [[Category: Lama L]] |
| - | [[Category: Patel, D J]] | + | [[Category: Patel DJ]] |
| - | [[Category: Tuschl, T]] | + | [[Category: Tuschl T]] |
| - | [[Category: Xie, W]] | + | [[Category: Xie W]] |
| - | [[Category: Cga]]
| + | |
| - | [[Category: Compound]]
| + | |
| - | [[Category: Core domain]]
| + | |
| - | [[Category: Dna binding protein]]
| + | |
| - | [[Category: Ru-521]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
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.[1] [2]
Publication Abstract from PubMed
The cyclic GMP-AMP synthase (cGAS)-cGAMP-STING pathway plays a key role in innate immunity, with cGAS sensing both pathogenic and mislocalized DNA in the cytoplasm. Human cGAS (h-cGAS) constitutes an important drug target for control of antiinflammatory responses that can contribute to the onset of autoimmune diseases. Recent studies have established that the positively charged N-terminal segment of cGAS contributes to enhancement of cGAS enzymatic activity as a result of DNA-induced liquid-phase condensation. We have identified an additional cGAS(CD)-DNA interface (labeled site-C; CD, catalytic domain) in the crystal structure of a human SRY.cGAS(CD)-DNA complex, with mutations along this basic site-C cGAS interface disrupting liquid-phase condensation, as monitored by cGAMP formation, gel shift, spin-down, and turbidity assays, as well as time-lapse imaging of liquid droplet formation. We expand on an earlier ladder model of cGAS dimers bound to a pair of parallel-aligned DNAs to propose a multivalent interaction-mediated cluster model to account for DNA-mediated condensation involving both the N-terminal domain of cGAS and the site-C cGAS-DNA interface. We also report the crystal structure of the h-cGAS(CD)-DNA complex containing a triple mutant that disrupts the site-C interface, with this complex serving as a future platform for guiding cGAS inhibitor development at the DNA-bound h-cGAS level. Finally, we solved the structure of RU.521 bound in two alternate alignments to apo h-cGAS(CD), thereby occupying more of the catalytic pocket and providing insights into further optimization of active-site-binding inhibitors.
Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation.,Xie W, Lama L, Adura C, Tomita D, Glickman JF, Tuschl T, Patel DJ Proc Natl Acad Sci U S A. 2019 May 29. pii: 1905013116. doi:, 10.1073/pnas.1905013116. PMID:31142647[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011 Apr 28;472(7344):481-5. doi: 10.1038/nature09907. Epub 2011 Apr 10. PMID:21478870 doi:10.1038/nature09907
- ↑ Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013 Feb 15;339(6121):786-91. doi: 10.1126/science.1232458. Epub 2012, Dec 20. PMID:23258413 doi:10.1126/science.1232458
- ↑ Xie W, Lama L, Adura C, Tomita D, Glickman JF, Tuschl T, Patel DJ. Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation. Proc Natl Acad Sci U S A. 2019 May 29. pii: 1905013116. doi:, 10.1073/pnas.1905013116. PMID:31142647 doi:http://dx.doi.org/10.1073/pnas.1905013116
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