22UK

Crystal structure of human cGAS in complex with NF023

Summary for 22UK

• Entry DOI: 10.2210/pdb22uk/pdb
• Descriptor: Cyclic GMP-AMP synthase, 8-({3-[({3-[(4,6,8-trisulfonaphthalen-1-yl)carbamoyl]phenyl}carbamoyl)amino]benzoyl}amino)naphthalene-1,3,5-trisulfonic acid, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• Functional Keywords: cgas, innate immune pathway, cgamp, suramin analogue, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 90141.76

Authors

Zhao, B.Y.,Huang, Y.X. (deposition date: 2026-01-23, release date: 2026-10-21)

Primary citation

An, X.,Wang, J.,Duan, B.,Xiao, Y.,Huang, Y.,Zhao, H.,Zhang, M.,Tao, K.,Wang, Q.,Du, F.,Zhu, L.,Zhao, B.
Suramin and its analogues are multi-functional inhibitors of cGAS.
J.Mol.Biol., :170044-170044, 2026

PubMed Abstract: Upon sensing double-stranded DNA, cyclic GMP-AMP synthase (cGAS) catalyzes ATP and GTP to synthesize the cyclic dinucleotide 2',3'-cGAMP, which subsequently activates stimulator of interferon genes (STING)-mediated immune responses. Modulation of cGAS catalytic activity is crucial for treating diseases associated with the cGAS-STING pathway. Here, we found that suramin and its analogues, such as NF023, can inhibit 2',3'-cGAMP synthesis by competitively binding to cGAS. Structural analysis of the cGAS-NF023 complex reveals that NF023 binds to the active-site cleft and DNA-binding sites of cGAS, which prevents substrate access to the active site, stabilizes the activation loop in an inactive conformation and blocks cGAS-DNA binding. In addition, both suramin and NF023 disrupt cGAS-DNA phase separation, thereby potentially impairing cytosolic DNA sensing and downstream signal transduction. These findings unveil the unique mechanisms underlying cGAS inhibition by suramin and its analogues and provide the structural basis for developing cGAS inhibitors.

PubMed: 42810574
DOI: 10.1016/j.jmb.2026.170044

Experimental method

X-RAY DIFFRACTION (2.55 Å)