9C8N

Crystal Structure of human cyclic GMP-AMP synthase in complex with AMPPNP and compound 1

これはPDB形式変換不可エントリーです。

9C8N の概要

• エントリーDOI: 10.2210/pdb9c8n/pdb
• 分子名称: Cyclic GMP-AMP synthase, 1-[(1S)-6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-methoxyethan-1-one, GLYCEROL, ... (7 entities in total)
• 機能のキーワード: dna sensor, nucleotidyltransferase, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43977.89

構造登録者

Wang, L.,Sietsema, D. (登録日: 2024-06-12, 公開日: 2025-04-02)

主引用文献

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

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: 40121343
DOI: 10.1038/s42004-025-01481-7

実験手法

X-RAY DIFFRACTION (1.55 Å)