6mjw

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Current revision

human cGAS catalytic domain bound with the inhibitor G150

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 <StructureSection load='6mjw' size='340' side='right'caption='[[6mjw]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mjw]] 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=6MJW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MJW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mjw]] 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=6MJW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MJW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JUJ: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'>JUJ</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]] 2.405&#8491;</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=JUJ: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'>JUJ</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=6mjw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mjw OCA], [https://pdbe.org/6mjw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mjw RCSB], [https://www.ebi.ac.uk/pdbsum/6mjw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mjw 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=6mjw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mjw OCA], [http://pdbe.org/6mjw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mjw RCSB], [http://www.ebi.ac.uk/pdbsum/6mjw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mjw ProSAT]</span></td></tr>
 </table>
 == 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;">
-== Publication Abstract from PubMed ==
-Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.
-Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression.,Lama L, Adura C, Xie W, Tomita D, Kamei T, Kuryavyi V, Gogakos T, Steinberg JI, Miller M, Ramos-Espiritu L, Asano Y, Hashizume S, Aida J, Imaeda T, Okamoto R, Jennings AJ, Michino M, Kuroita T, Stamford A, Gao P, Meinke P, Glickman JF, Patel DJ, Tuschl T Nat Commun. 2019 May 21;10(1):2261. doi: 10.1038/s41467-019-08620-4. PMID:31113940<ref>PMID:31113940</ref>
+==See Also==
+*[[Cyclic GMP-AMP synthase 3D synthase|Cyclic GMP-AMP synthase 3D synthase]]
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 6mjw" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Cyclic GMP-AMP synthase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Adura, C]]
+[[Category: Adura C]]
-[[Category: Aida, J]]
+[[Category: Aida J]]
-[[Category: Asano, Y]]
+[[Category: Asano Y]]
-[[Category: Gao, P]]
+[[Category: Gao P]]
-[[Category: Glickman, J F]]
+[[Category: Glickman JF]]
-[[Category: Gogakos, T]]
+[[Category: Gogakos T]]
-[[Category: Hashizume, S]]
+[[Category: Hashizume S]]
-[[Category: Imaeda, T]]
+[[Category: Imaeda T]]
-[[Category: Jennings, A J]]
+[[Category: Jennings AJ]]
-[[Category: Kamei, T]]
+[[Category: Kamei T]]
-[[Category: Kuroita, T]]
+[[Category: Kuroita T]]
-[[Category: Kuryavyi, V]]
+[[Category: Kuryavyi V]]
-[[Category: Lama, L]]
+[[Category: Lama L]]
-[[Category: Meinke, P]]
+[[Category: Meinke P]]
-[[Category: Michinom, M]]
+[[Category: Michinom M]]
-[[Category: Miller, M]]
+[[Category: Miller M]]
-[[Category: Okamoto, R]]
+[[Category: Okamoto R]]
-[[Category: Patel, D J]]
+[[Category: Patel DJ]]
-[[Category: Ramos-Espiritu, L]]
+[[Category: Ramos-Espiritu L]]
-[[Category: Stamford, A]]
+[[Category: Stamford A]]
-[[Category: Steinberg, J I]]
+[[Category: Steinberg JI]]
-[[Category: Tomita, D]]
+[[Category: Tomita D]]
-[[Category: Tuschl, T]]
+[[Category: Tuschl T]]
-[[Category: Xie, W]]
+[[Category: Xie W]]
-[[Category: Dna sensor]]
-[[Category: Human cga]]
-[[Category: Immune system]]
-[[Category: Inhibitor]]
-[[Category: Transferase-transferase inhibitor complex]]

6mjw

From Proteopedia

Current revision

human cGAS catalytic domain bound with the inhibitor G150

Structural highlights

Function

See Also

References

Contents

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