5CFM

Crystal structure of anemone STING (Nematostella vectensis) in complex with 3', 3' cGAMP, c[G(3', 5')pA(3', 5')p]

Summary for 5CFM

• Entry DOI: 10.2210/pdb5cfm/pdb
• Related: 5CFL 5CFN 5CFO 5CFP 5CFQ 5CFR
• Descriptor: Stimulator of Interferon Genes, 2-amino-9-[(2R,3R,3aS,5R,7aR,9R,10R,10aS,12R,14aR)-9-(6-amino-9H-purin-9-yl)-3,5,10,12-tetrahydroxy-5,12-dioxidooctahydro-2H,7H-difuro[3,2-d:3',2'-j][1,3,7,9,2,8]tetraoxadiphosphacyclododecin-2-yl]-1,9-dihydro-6H-purin-6-one, CITRATE ANION, ... (4 entities in total)
• Functional Keywords: sting, cyclic-dinucleotide binding domain, immune system
• Biological source: Nematostella vectensis (Starlet sea anemone)
• Total number of polymer chains: 2
• Total formula weight: 44882.26

Authors

Kranzusch, P.J.,Wilson, S.C.,Lee, A.S.Y.,Berger, J.M.,Doudna, J.A.,Vance, R.E. (deposition date: 2015-07-08, release date: 2015-08-26, Last modification date: 2024-03-06)

Primary citation

Kranzusch, P.J.,Wilson, S.C.,Lee, A.S.,Berger, J.M.,Doudna, J.A.,Vance, R.E.
Ancient Origin of cGAS-STING Reveals Mechanism of Universal 2',3' cGAMP Signaling.
Mol.Cell, 59:891-903, 2015

PubMed Abstract: In humans, the cGAS-STING immunity pathway signals in response to cytosolic DNA via 2',3' cGAMP, a cyclic dinucleotide (CDN) second messenger containing mixed 2'-5' and 3'-5' phosphodiester bonds. Prokaryotes also produce CDNs, but these are exclusively 3' linked, and thus the evolutionary origins of human 2',3' cGAMP signaling are unknown. Here we illuminate the ancient origins of human cGAMP signaling by discovery of a functional cGAS-STING pathway in Nematostella vectensis, an anemone species >500 million years diverged from humans. Anemone cGAS appears to produce a 3',3' CDN that anemone STING recognizes through nucleobase-specific contacts not observed in human STING. Nevertheless, anemone STING binds mixed-linkage 2',3' cGAMP indistinguishably from human STING, trapping a unique structural conformation not induced by 3',3' CDNs. These results reveal that human mixed-linkage cGAMP achieves universal signaling by exploiting a deeply conserved STING conformational intermediate, providing critical insight for therapeutic targeting of the STING pathway.

PubMed: 26300263
DOI: 10.1016/j.molcel.2015.07.022

Experimental method

X-RAY DIFFRACTION (1.994 Å)