Summary for 6NAO
| Entry DOI | 10.2210/pdb6nao/pdb |
| Related | 5V8H 5V8J 5V8O |
| Descriptor | CYCLIC GMP-AMP SYNTHASE, ZINC ION, (1R,2S)-2-[(7-hydroxy-5-phenylpyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]cyclohexane-1-carboxylic acid, ... (4 entities in total) |
| Functional Keywords | cgas, sting, cgamp, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 85701.42 |
| Authors | Hall, J. (deposition date: 2018-12-06, release date: 2018-12-19, Last modification date: 2024-03-13) |
| Primary citation | Hall, J.,Brault, A.,Vincent, F.,Weng, S.,Wang, H.,Dumlao, D.,Aulabaugh, A.,Aivazian, D.,Castro, D.,Chen, M.,Culp, J.,Dower, K.,Gardner, J.,Hawrylik, S.,Golenbock, D.,Hepworth, D.,Horn, M.,Jones, L.,Jones, P.,Latz, E.,Li, J.,Lin, L.L.,Lin, W.,Lin, D.,Lovering, F.,Niljanskul, N.,Nistler, R.,Pierce, B.,Plotnikova, O.,Schmitt, D.,Shanker, S.,Smith, J.,Snyder, W.,Subashi, T.,Trujillo, J.,Tyminski, E.,Wang, G.,Wong, J.,Lefker, B.,Dakin, L.,Leach, K. Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay. PLoS ONE, 12:e0184843-, 2017 Cited by PubMed Abstract: Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors. PubMed: 28934246DOI: 10.1371/journal.pone.0184843 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.23 Å) |
Structure validation
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