4JC5

Immune activator bound to receptor

Summary for 4JC5

• Entry DOI: 10.2210/pdb4jc5/pdb
• Descriptor: Transmembrane protein 173, (9-oxoacridin-10(9H)-yl)acetic acid (3 entities in total)
• Functional Keywords: innate immune receptor, immune system
• Biological source: Mus musculus (mouse)
• Cellular location: Endoplasmic reticulum membrane ; Multi-pass membrane protein : Q3TBT3
• Total number of polymer chains: 2
• Total formula weight: 46320.69

Authors

Deimling, T.,Hopfner, K.P. (deposition date: 2013-02-21, release date: 2013-05-08, Last modification date: 2024-02-28)

Primary citation

Cavlar, T.,Deimling, T.,Ablasser, A.,Hopfner, K.P.,Hornung, V.
Species-specific detection of the antiviral small-molecule compound CMA by STING.
Embo J., 32:1440-1450, 2013

PubMed Abstract: Extensive research on antiviral small molecules starting in the early 1970s has led to the identification of 10-carboxymethyl-9-acridanone (CMA) as a potent type I interferon (IFN) inducer. Up to date, the mode of action of this antiviral molecule has remained elusive. Here we demonstrate that CMA mediates a cell-intrinsic type I IFN response, depending on the ER-resident protein STING. CMA directly binds to STING and triggers a strong antiviral response through the TBK1/IRF3 route. Interestingly, while CMA displays extraordinary activity in phosphorylating IRF3 in the murine system, CMA fails to activate human cells that are otherwise responsive to STING ligands. This failure to activate human STING can be ascribed to its inability to bind to the C-terminal ligand-binding domain of human STING. Crystallographic studies show that two CMA molecules bind to the central Cyclic diguanylate (c-diGMP)-binding pocket of the STING dimer and fold the lid region in a fashion similar, but partially distinct, to c-diGMP. Altogether, these results provide novel insight into ligand-sensing properties of STING and, furthermore, unravel unexpected species-specific differences of this innate sensor.

PubMed: 23604073
DOI: 10.1038/emboj.2013.86

Experimental method

X-RAY DIFFRACTION (2.75 Å)