6cta: Difference between revisions
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==Structure of the human cGAS-DNA complex with ATP== | ==Structure of the human cGAS-DNA complex with ATP== | ||
<StructureSection load='6cta' size='340' side='right' caption='[[6cta]], [[Resolution|resolution]] 2.78Å' scene=''> | <StructureSection load='6cta' size='340' side='right'caption='[[6cta]], [[Resolution|resolution]] 2.78Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6cta]] is a 3 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6cta]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CTA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CTA FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.779Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=6cta FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cta OCA], [https://pdbe.org/6cta PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cta RCSB], [https://www.ebi.ac.uk/pdbsum/6cta PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cta ProSAT]</span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6cta" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6cta" 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: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Synthetic construct]] | ||
[[Category: | [[Category: Kranzusch PJ]] | ||
[[Category: Mekalanos | [[Category: Mekalanos JJ]] | ||
[[Category: Morehouse | [[Category: Morehouse BR]] | ||
[[Category: Whiteley | [[Category: Whiteley AT]] | ||
[[Category: Zhou | [[Category: Zhou W]] | ||
[[Category: | [[Category: De Oliveira Mann CC]] | ||
Latest revision as of 18:10, 4 October 2023
Structure of the human cGAS-DNA complex with ATPStructure of the human cGAS-DNA complex with ATP
Structural highlights
FunctionCGAS_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 PubMedCyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS-DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP-AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS-DNA complex to enable structure-guided design of cGAS therapeutics. Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance.,Zhou W, Whiteley AT, de Oliveira Mann CC, Morehouse BR, Nowak RP, Fischer ES, Gray NS, Mekalanos JJ, Kranzusch PJ Cell. 2018 Jul 12;174(2):300-311.e11. doi: 10.1016/j.cell.2018.06.026. PMID:30007416[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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