6y5d: Difference between revisions
New page: '''Unreleased structure''' The entry 6y5d is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Structure of human cGAS (K394E) bound to the nucleosome== | ||
<StructureSection load='6y5d' size='340' side='right'caption='[[6y5d]], [[Resolution|resolution]] 4.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6y5d]] is a 22 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=6Y5D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Y5D FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTD:PENTANEDIAL'>PTD</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=6y5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y5d OCA], [https://pdbe.org/6y5d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6y5d RCSB], [https://www.ebi.ac.uk/pdbsum/6y5d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6y5d ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/H32_HUMAN H32_HUMAN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The DNA sensor cGAS initiates innate immune responses following microbial infection, cellular stress, and cancer(1). Upon activation by double-stranded DNA, cytosolic cGAS produces 2'3' cyclic GMP-AMP and triggers inflammatory cytokine and type I interferon (IFN) induction(2-7). cGAS is also present inside the cell nucleus replete with genomic DNA(8), where chromatin has been implicated in restricting its enzymatic activity(9). However, the structural basis for cGAS inhibition by chromatin has remained unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes at 3.1 A resolution. cGAS makes extensive contacts with both the acidic patch of the histone H2A-H2B heterodimer and nucleosomal DNA. The structural and complementary biochemical analysis also finds cGAS engaged to a second nucleosome in trans. Mechanistically, nucleosome binding locks cGAS in a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are necessary and sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash cGAS activity on genomic DNA in living cells. Our work uncovers the structural basis of cGAS interaction with chromatin and defines a compelling mechanism that permits self-nonself discrimination of genomic DNA by cGAS. | |||
Structural mechanism of cGAS inhibition by the nucleosome.,Pathare GR, Decout A, Gluck S, Cavadini S, Makasheva K, Hovius R, Kempf G, Weiss J, Kozicka Z, Guey B, Melenec P, Fierz B, Thoma NH, Ablasser A Nature. 2020 Sep 10. pii: 10.1038/s41586-020-2750-6. doi:, 10.1038/s41586-020-2750-6. PMID:32911482<ref>PMID:32911482</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6y5d" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cyclic GMP-AMP synthase 3D synthase|Cyclic GMP-AMP synthase 3D synthase]] | |||
*[[Histone 3D structures|Histone 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Cavadini S]] | |||
[[Category: Kempf G]] | |||
[[Category: Pathare GR]] | |||
[[Category: Thoma NH]] | |||
Latest revision as of 13:44, 23 October 2024
Structure of human cGAS (K394E) bound to the nucleosomeStructure of human cGAS (K394E) bound to the nucleosome
Structural highlights
FunctionPublication Abstract from PubMedThe DNA sensor cGAS initiates innate immune responses following microbial infection, cellular stress, and cancer(1). Upon activation by double-stranded DNA, cytosolic cGAS produces 2'3' cyclic GMP-AMP and triggers inflammatory cytokine and type I interferon (IFN) induction(2-7). cGAS is also present inside the cell nucleus replete with genomic DNA(8), where chromatin has been implicated in restricting its enzymatic activity(9). However, the structural basis for cGAS inhibition by chromatin has remained unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes at 3.1 A resolution. cGAS makes extensive contacts with both the acidic patch of the histone H2A-H2B heterodimer and nucleosomal DNA. The structural and complementary biochemical analysis also finds cGAS engaged to a second nucleosome in trans. Mechanistically, nucleosome binding locks cGAS in a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are necessary and sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash cGAS activity on genomic DNA in living cells. Our work uncovers the structural basis of cGAS interaction with chromatin and defines a compelling mechanism that permits self-nonself discrimination of genomic DNA by cGAS. Structural mechanism of cGAS inhibition by the nucleosome.,Pathare GR, Decout A, Gluck S, Cavadini S, Makasheva K, Hovius R, Kempf G, Weiss J, Kozicka Z, Guey B, Melenec P, Fierz B, Thoma NH, Ablasser A Nature. 2020 Sep 10. pii: 10.1038/s41586-020-2750-6. doi:, 10.1038/s41586-020-2750-6. PMID:32911482[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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