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==Discovery of a high affinity inhibitor of cGAS==
==Discovery of a high affinity inhibitor of cGAS==
<StructureSection load='6nao' size='340' side='right' caption='[[6nao]], [[Resolution|resolution]] 3.23&Aring;' scene=''>
<StructureSection load='6nao' size='340' side='right'caption='[[6nao]], [[Resolution|resolution]] 3.23&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6nao]] is a 2 chain structure. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5v8n 5v8n]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NAO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NAO FirstGlance]. <br>
<table><tr><td colspan='2'>[[6nao]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5v8n 5v8n]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NAO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=KHM:(1R,2S)-2-[(7-hydroxy-5-phenylpyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]cyclohexane-1-carboxylic+acid'>KHM</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]] 3.23&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v8j|5v8j]], [[5v8h|5v8h]], [[5v8o|5v8o]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KHM:(1R,2S)-2-[(7-hydroxy-5-phenylpyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]cyclohexane-1-carboxylic+acid'>KHM</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=6nao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nao OCA], [https://pdbe.org/6nao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nao RCSB], [https://www.ebi.ac.uk/pdbsum/6nao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nao 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=6nao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nao OCA], [http://pdbe.org/6nao PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nao RCSB], [http://www.ebi.ac.uk/pdbsum/6nao PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nao 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;">
== Publication Abstract from PubMed ==
Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors.


Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay.,Hall J, Brault A, Vincent F, Weng S, Wang H, Dumlao D, Aulabaugh A, Aivazian D, Castro D, Chen M, Culp J, Dower K, Gardner J, Hawrylik S, Golenbock D, Hepworth D, Horn M, Jones L, Jones P, Latz E, Li J, Lin LL, Lin W, Lin D, Lovering F, Niljanskul N, Nistler R, Pierce B, Plotnikova O, Schmitt D, Shanker S, Smith J, Snyder W, Subashi T, Trujillo J, Tyminski E, Wang G, Wong J, Lefker B, Dakin L, Leach K PLoS One. 2017 Sep 21;12(9):e0184843. doi: 10.1371/journal.pone.0184843., eCollection 2017. PMID:28934246<ref>PMID:28934246</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 6nao" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Cyclic GMP-AMP synthase]]
[[Category: Homo sapiens]]
[[Category: Hall, J]]
[[Category: Large Structures]]
[[Category: Cga]]
[[Category: Hall J]]
[[Category: Cgamp]]
[[Category: Sting]]
[[Category: Transferase]]
[[Category: Transferase-transferase inhibitor complex]]

Latest revision as of 17:47, 13 March 2024

Discovery of a high affinity inhibitor of cGASDiscovery of a high affinity inhibitor of cGAS

Structural highlights

6nao is a 2 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 5v8n. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.23Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

See Also

References

  1. ↑ 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
  2. ↑ 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

6nao, resolution 3.23Å

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