9C8T
Crystal Structure of human cyclic GMP-AMP synthase in complex with AMPPNP and compound 2
Summary for 9C8T
| Entry DOI | 10.2210/pdb9c8t/pdb |
| Related | 9C8N |
| Descriptor | Cyclic GMP-AMP synthase, MAGNESIUM ION, ZINC ION, ... (7 entities in total) |
| Functional Keywords | dna sensor, nucleotidyltransferase, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43949.84 |
| Authors | |
| Primary citation | Skeldon, A.M.,Wang, L.,Sgarioto, N.,Beveridge, R.E.,Chan, S.,Dorich, S.,Dumais, V.,Fradet, N.,Gaudreault, S.,LeGros, P.,McKay, D.,Seliniotakis, R.,Sietsema, D.V.,Zhang, L.,Boily, M.O.,Burch, J.D.,Caron, A.,Fader, L.D.,Lama, L.,Xie, W.,Patel, D.J.,Tuschl, T.,Crackower, M.A.,Pike, K.A. Structural insight into the cGAS active site explains differences between therapeutically relevant species. Commun Chem, 8:88-88, 2025 Cited by PubMed Abstract: 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. PubMed: 40121343DOI: 10.1038/s42004-025-01481-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.47 Å) |
Structure validation
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