6y5e | pdb_00006y5e

Structure of human cGAS (K394E) bound to the nucleosome (focused refinement of cGAS-NCP subcomplex)

spinqualitylabelsall models 6y5e, resolution 3.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6y5e is a 11 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: Electron Microscopy, Resolution 3.15Å Ligands: PTD, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function H32_HUMAN 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cyclic GMP-AMP synthase 3D synthase Histone 3D structures

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