6MJX

human cGAS catalytic domain bound with cGAMP

Summary for 6MJX

• Entry DOI: 10.2210/pdb6mjx/pdb
• Descriptor: Cyclic GMP-AMP synthase, cGAMP, ZINC ION (3 entities in total)
• Functional Keywords: human cgas, dna sensor, immune system, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 44225.87

Authors

Lama, L.,Adura, C.,Xie, W.,Tomita, D.,Kamei, T.,Kuryavyi, V.,Gogakos, T.,Steinberg, J.I.,Miller, M.,Ramos-Espiritu, L.,Asano, Y.,Hashizume, S.,Aida, J.,Imaeda, T.,Okamoto, R.,Jennings, A.J.,Michinom, M.,Kuroita, T.,Stamford, A.,Gao, P.,Meinke, P.,Glickman, J.F.,Patel, D.J.,Tuschl, T. (deposition date: 2018-09-23, release date: 2019-05-29, Last modification date: 2024-03-13)

Primary citation

Lama, L.,Adura, C.,Xie, W.,Tomita, D.,Kamei, T.,Kuryavyi, V.,Gogakos, T.,Steinberg, J.I.,Miller, M.,Ramos-Espiritu, L.,Asano, Y.,Hashizume, S.,Aida, J.,Imaeda, T.,Okamoto, R.,Jennings, A.J.,Michino, M.,Kuroita, T.,Stamford, A.,Gao, P.,Meinke, P.,Glickman, J.F.,Patel, D.J.,Tuschl, T.
Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression.
Nat Commun, 10:2261-2261, 2019

PubMed Abstract: Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.

PubMed: 31113940
DOI: 10.1038/s41467-019-08620-4

Experimental method

X-RAY DIFFRACTION (2.6 Å)