6x5a

The mouse cGAS catalytic domain binding to human nucleosome that purified from HEK293T cells

spinqualitylabelsall models 6x5a, resolution 4.36Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6x5a is a 11 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 4.36Å Ligands: ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function H32_HUMAN Publication Abstract from PubMed Pathogen-derived nucleic acids induce potent innate immune responses(1-6). Cyclic GMP-AMP synthase (cGAS) is a dsDNA sensor that catalyzes the synthesis of a cyclic dinucleotide cGAMP, which mediates the induction of type I interferons through the STING-TBK1-IRF3 signaling axis(7-11). It was widely accepted that cGAS is not reactive to self-DNA due to its cytosolic localization(2,12,13). However, recent studies revealed that cGAS is mostly localized in the nucleus and tight nuclear tethering keeps cGAS inactive(14-18). Here we show that cGAS binds to nucleosomes with nanomolar affinity and nucleosome binding potently inhibits the catalytic activity of cGAS. To elucidate the molecular basis of cGAS inactivation by nuclear tethering, we have determined the structure of mouse cGAS bound to human nucleosome by cryo-EM. The structure shows that cGAS binds to a negatively charged acidic patch formed by histone H2A and H2B via its second DNA binding site(19). High affinity nucleosome binding blocks dsDNA binding and keeps cGAS in an inactive conformation. Mutations of cGAS that disrupt nucleosome binding dramatically affect cGAS mediated signaling in cells. The Molecular Basis of Tight Nuclear Tethering and Inactivation of cGAS.,Zhao B, Xu P, Rowlett CM, Jing T, Shinde O, Lei Y, West AP, Liu WR, Li P Nature. 2020 Sep 10. pii: 10.1038/s41586-020-2749-z. doi:, 10.1038/s41586-020-2749-z. PMID:32911481 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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