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9mdd

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Crystal Structure of human cyclic GMP-AMP synthase (cGAS) in complex with compound 23; (S)-1-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2-methoxyethan-1-one

Structural highlights

9mdd 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 1.6Å
Ligands:	, , ,
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.^[1] ^[2]

Publication Abstract from PubMed

Using a high-throughput screening (HTS) approach, a new GTP-site binding pyridine-carboxylate series of cGAS inhibitors was discovered. The biochemical potency of this new pyridine carboxylate series was improved 166-fold from the original hit to double-digit nanomolar levels using structure-based design insights, but the series was found to suffer from low permeability and low bioavailability. A structure-based hybridization of the metal-binding motifs of the pyridine carboxylate series and our previously disclosed tetrahydrocarboline GTP-site ligand 23 identified pyrimidine amide compound 36. Compound 36 is potent against both human and mouse cGAS isoforms and has a favorable pharmacokinetic (PK) profile in mice. Additionally, compound 36 displayed a dose-dependent reduction in cGAMP production in a ConA pharmacodynamic mouse model of acute liver injury, demonstrating potential utility as an in vivo tool compound for further investigation of the cGAS pathway.

Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.,Cyr P, Fader LD, Burch JD, Pike KA, Sietsema DV, Boily MO, Ciblat S, Sgarioto N, Skeldon AM, Gaudreault S, Le Gros P, Dumais V, McKay DJJ, Abraham NS, Seliniotakis R, Beveridge RE ACS Med Chem Lett. 2024 Nov 25;15(12):2201-2209. doi: , 10.1021/acsmedchemlett.4c00471. eCollection 2024 Dec 12. PMID:39691514^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011 Apr 28;472(7344):481-5. doi: 10.1038/nature09907. Epub 2011 Apr 10. PMID:21478870 doi:10.1038/nature09907
↑ Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013 Feb 15;339(6121):786-91. doi: 10.1126/science.1232458. Epub 2012, Dec 20. PMID:23258413 doi:10.1126/science.1232458
↑ Cyr P, Fader LD, Burch JD, Pike KA, Sietsema DV, Boily MO, Ciblat S, Sgarioto N, Skeldon AM, Gaudreault S, Le Gros P, Dumais V, McKay DJJ, Abraham NS, Seliniotakis R, Beveridge RE. Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization. ACS Med Chem Lett. 2024 Nov 25;15(12):2201-2209. PMID:39691514 doi:10.1021/acsmedchemlett.4c00471