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6edc

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'''Unreleased structure'''
 
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The entry 6edc is ON HOLD
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==hcGAS-16bp dsDNA complex==
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<StructureSection load='6edc' size='340' side='right'caption='[[6edc]], [[Resolution|resolution]] 2.71&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6edc]] is a 3 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=6EDC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EDC FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.712&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6edc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6edc OCA], [https://pdbe.org/6edc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6edc RCSB], [https://www.ebi.ac.uk/pdbsum/6edc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6edc ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The cyclic GMP-AMP synthase (cGAS)-cGAMP-STING pathway plays a key role in innate immunity, with cGAS sensing both pathogenic and mislocalized DNA in the cytoplasm. Human cGAS (h-cGAS) constitutes an important drug target for control of antiinflammatory responses that can contribute to the onset of autoimmune diseases. Recent studies have established that the positively charged N-terminal segment of cGAS contributes to enhancement of cGAS enzymatic activity as a result of DNA-induced liquid-phase condensation. We have identified an additional cGAS(CD)-DNA interface (labeled site-C; CD, catalytic domain) in the crystal structure of a human SRY.cGAS(CD)-DNA complex, with mutations along this basic site-C cGAS interface disrupting liquid-phase condensation, as monitored by cGAMP formation, gel shift, spin-down, and turbidity assays, as well as time-lapse imaging of liquid droplet formation. We expand on an earlier ladder model of cGAS dimers bound to a pair of parallel-aligned DNAs to propose a multivalent interaction-mediated cluster model to account for DNA-mediated condensation involving both the N-terminal domain of cGAS and the site-C cGAS-DNA interface. We also report the crystal structure of the h-cGAS(CD)-DNA complex containing a triple mutant that disrupts the site-C interface, with this complex serving as a future platform for guiding cGAS inhibitor development at the DNA-bound h-cGAS level. Finally, we solved the structure of RU.521 bound in two alternate alignments to apo h-cGAS(CD), thereby occupying more of the catalytic pocket and providing insights into further optimization of active-site-binding inhibitors.
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Authors:
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Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation.,Xie W, Lama L, Adura C, Tomita D, Glickman JF, Tuschl T, Patel DJ Proc Natl Acad Sci U S A. 2019 May 29. pii: 1905013116. doi:, 10.1073/pnas.1905013116. PMID:31142647<ref>PMID:31142647</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6edc" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Cyclic GMP-AMP synthase 3D synthase|Cyclic GMP-AMP synthase 3D synthase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Adura C]]
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[[Category: Glickman JF]]
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[[Category: Lama L]]
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[[Category: Patel DJ]]
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[[Category: Tuschl T]]
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[[Category: Xie W]]

Current revision

hcGAS-16bp dsDNA complex

PDB ID 6edc

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