9c3g

From Proteopedia

(Difference between revisions)

Current revision

human cGAS core domain (K427E/K428E) bound to Cladophorol A

Structural highlights

9c3g is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.75Å
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]

Publication Abstract from PubMed

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is an enzyme sensor of double-stranded DNA (dsDNA) that serves to trigger activation of the cGAS-stimulator of interferon genes (STING) pathway. Excessive activation of this pathway has been demonstrated to contribute to various forms of inflammatory disease. As such, cGAS has arisen as a potential therapeutic target with broad potential applications. Using a pathway-targeted cell-based screening approach, we identified the natural product Cladophorol-A as a new class of non-cytotoxic cGAS inhibitor (cell-based IC(50) = 370 nM). An X-ray co-crystal structure at 2.75 A resolution revealed that Cladophorol-A inhibits cGAS by binding to its active site within the conserved adenosine nucleobase binding site.

Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase.,Kissai M, Chin EN, Martinez-Pena F, Sulpizio A, Stout EP, Usui I, Barmare F, Sanchez B, Esquenazi E, Stanfield RL, Wilson IA, Lairson LL Bioorg Med Chem Lett. 2025 Jan 1;115:130007. doi: 10.1016/j.bmcl.2024.130007. , Epub 2024 Nov 7. PMID:39521150^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Kissai M, Chin EN, Martínez-Peña F, Sulpizio A, Stout EP, Usui I, Barmare F, Sanchez B, Esquenazi E, Stanfield RL, Wilson IA, Lairson LL. Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase. Bioorg Med Chem Lett. 2025 Jan 1;115:130007. PMID:39521150 doi:10.1016/j.bmcl.2024.130007

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9c3g"

Categories: Homo sapiens | Large Structures | Kissai M | Lairson LL | Stanfield RL

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9c3g is ON HOLD  until Paper Publication
+==human cGAS core domain (K427E/K428E) bound to Cladophorol A==
+<StructureSection load='9c3g' size='340' side='right'caption='[[9c3g]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9c3g]] 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=9C3G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9C3G FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.75&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AVI:2,3,8,9-tetrakis(oxidanyl)benzo[c]chromen-6-one'>A1AVI</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=9c3g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9c3g OCA], [https://pdbe.org/9c3g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9c3g RCSB], [https://www.ebi.ac.uk/pdbsum/9c3g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9c3g ProSAT]</span></td></tr>
+</table>
+== Function ==
+[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 guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is an enzyme sensor of double-stranded DNA (dsDNA) that serves to trigger activation of the cGAS-stimulator of interferon genes (STING) pathway. Excessive activation of this pathway has been demonstrated to contribute to various forms of inflammatory disease. As such, cGAS has arisen as a potential therapeutic target with broad potential applications. Using a pathway-targeted cell-based screening approach, we identified the natural product Cladophorol-A as a new class of non-cytotoxic cGAS inhibitor (cell-based IC(50) = 370 nM). An X-ray co-crystal structure at 2.75 A resolution revealed that Cladophorol-A inhibits cGAS by binding to its active site within the conserved adenosine nucleobase binding site.
-Authors: Kissai, M., Stanfield, R.L., Lairson, L.L.
+Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase.,Kissai M, Chin EN, Martinez-Pena F, Sulpizio A, Stout EP, Usui I, Barmare F, Sanchez B, Esquenazi E, Stanfield RL, Wilson IA, Lairson LL Bioorg Med Chem Lett. 2025 Jan 1;115:130007. doi: 10.1016/j.bmcl.2024.130007. , Epub 2024 Nov 7. PMID:39521150<ref>PMID:39521150</ref>
-Description: human cGAS core domain (K427E/K428E) bound to Cladophorol A
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Lairson, L.L]]
+<div class="pdbe-citations 9c3g" style="background-color:#fffaf0;"></div>
-[[Category: Stanfield, R.L]]
+== References ==
-[[Category: Kissai, M]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Kissai M]]
+[[Category: Lairson LL]]
+[[Category: Stanfield RL]]

9c3g

From Proteopedia

Current revision

human cGAS core domain (K427E/K428E) bound to Cladophorol A

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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