5CFR: Crystal Structure Of Anemone Sting (nematostella Vectensis) In Apo 'unrotated' Closed Conformation

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.
PDB ID: 5CFRDownload
MMDB ID: 132142
PDB Deposition Date: 2015/7/8
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2.85  Å
Source Organism:
Similar Structures:
Biological Unit for 5CFR: dimeric; determined by author and by software (PISA)
Molecular Components in 5CFR
Label Count Molecule
Proteins (2 molecules)
Stimulator of Interferon Genes(Gene symbol: NEMVEDRAFT_v1g246111)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

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