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5xze

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Revision as of 07:01, 14 October 2020

Mouse cGAS bound to the inhibitor RU332

Structural highlights

5xze is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Cyclic GMP-AMP synthase, with EC number 2.7.7.86
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5xze"

@@ Line 1: / Line 1: @@
 ==Mouse cGAS bound to the inhibitor RU332==
-<StructureSection load='5xze' size='340' side='right' caption='[[5xze]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
+<StructureSection load='5xze' size='340' side='right'caption='[[5xze]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5xze]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XZE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XZE FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5xze]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XZE OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5XZE FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AE7:(3R)-3-[1-(3H-1lambda~4~,3-benzothiazol-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]-2-benzofuran-1(3H)-one'>AE7</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AE7:(3R)-3-[1-(3H-1lambda~4~,3-benzothiazol-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]-2-benzofuran-1(3H)-one'>AE7</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5xze FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xze OCA], [http://pdbe.org/5xze PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xze RCSB], [http://www.ebi.ac.uk/pdbsum/5xze PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xze ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5xze FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xze OCA], [http://pdbe.org/5xze PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xze RCSB], [http://www.ebi.ac.uk/pdbsum/5xze PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xze ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5xze" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cyclic GMP-AMP synthase 3D synthase|Cyclic GMP-AMP synthase 3D synthase]]
 == References ==
 <references/>
@@ Line 24: / Line 27: @@
 </StructureSection>
 [[Category: Cyclic GMP-AMP synthase]]
+[[Category: Large Structures]]
 [[Category: Adura, C]]
 [[Category: Aida, J]]

5xze

From Proteopedia

Revision as of 07:01, 14 October 2020

Mouse cGAS bound to the inhibitor RU332

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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