9c8t | pdb_00009c8t

Crystal Structure of human cyclic GMP-AMP synthase in complex with AMPPNP and compound 2

spinqualitylabelsall models 9c8t, resolution 1.47Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9c8t is a 1 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: X-ray diffraction, Resolution 1.47Å Ligands: ANP, GOL, JUJ, MG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 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. Publication Abstract from PubMed Cyclic GMP-AMP synthase (cGAS) is an intracellular sensor of double-stranded DNA that triggers a pro-inflammatory response upon binding. The interest in cGAS as a drug discovery target has increased substantially over the past decade due to growing evidence linking its activation to numerous peripheral and neurological diseases. Here, we report the binding mode of previously described cGAS inhibitors while also uncovering the structural basis for the interspecies potency shifts within this chemotype. A single threonine to isoleucine substitution between human and mouse cGAS drives compound activity, as demonstrated by biochemical, cellular, and in vivo studies. Finally, we utilize a structurally enabled design approach to engineer a novel chemical inhibitor with excellent potency for both human and mouse enzymes by targeting key interactions within the enzyme active site. Overall, this work provides the framework for rational optimization of cGAS inhibitors and potential preclinical translational strategies. Structural insight into the cGAS active site explains differences between therapeutically relevant species.,Skeldon AM, Wang L, Sgarioto N, Beveridge RE, Chan S, Dorich S, Dumais V, Fradet N, Gaudreault S, LeGros P, McKay D, Seliniotakis R, Sietsema DV, Zhang L, Boily MO, Burch JD, Caron A, Fader LD, Lama L, Xie W, Patel DJ, Tuschl T, Crackower MA, Pike KA Commun Chem. 2025 Mar 22;8(1):88. doi: 10.1038/s42004-025-01481-7. PMID:40121343 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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