9c3g
human cGAS core domain (K427E/K428E) bound to Cladophorol A
Structural highlights
FunctionCGAS_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.[1] [2] Publication Abstract from PubMedCyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is an enzyme sensor of double-stranded DNA (dsDNA) that serves to trigger activation of the cGAS-stimulator of interferon genes (STING) pathway. Excessive activation of this pathway has been demonstrated to contribute to various forms of inflammatory disease. As such, cGAS has arisen as a potential therapeutic target with broad potential applications. Using a pathway-targeted cell-based screening approach, we identified the natural product Cladophorol-A as a new class of non-cytotoxic cGAS inhibitor (cell-based IC(50) = 370 nM). An X-ray co-crystal structure at 2.75 A resolution revealed that Cladophorol-A inhibits cGAS by binding to its active site within the conserved adenosine nucleobase binding site. Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase.,Kissai M, Chin EN, Martinez-Pena F, Sulpizio A, Stout EP, Usui I, Barmare F, Sanchez B, Esquenazi E, Stanfield RL, Wilson IA, Lairson LL Bioorg Med Chem Lett. 2025 Jan 1;115:130007. doi: 10.1016/j.bmcl.2024.130007. , Epub 2024 Nov 7. PMID:39521150[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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