Journal
CELL
Volume 154, Issue 4, Pages 748-762Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.07.023
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Funding
- Abby Rockefeller Mauze Trust
- Maloris Foundation
- STARR Foundation
- HHMI
- DFG [BA3544/1-1, SFB670, SFB704]
- NIH [GM79760, R56AI095692, GM42498]
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Binding of dsDNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) triggers formation of the metazoan second messenger c[G(2',5')pA(3',5')p], which binds the signaling protein STING with subsequent activation of the interferon (IFN) pathway. We show that human hSTING H232 adopts a closed conformation upon binding c[G(2',5') pA(3',5') p] and its linkage isomer c[G(2',5') pA(2',5') p], as does mouse mSting(R231) on binding c[G(2',5') pA(3',5') p], c[G(3',5') pA(3',5') p] and the antiviral agent DMXAA, leading to similar closed conformations. Comparing hSTING to mSting, 2',5'-linkage-containing cGAMP isomers were more specific triggers of the IFN pathway compared to the all-3',5'-linkage isomer. Guided by structural information, we identified a unique point mutation (S162A) placed within the cyclic-dinucleotide-binding site of hSTING that rendered it sensitive to the otherwise mouse-specific drug DMXAA, a conclusion validated by binding studies. Our structural and functional analysis highlights the unexpected versatility of STING in the recognition of natural and synthetic ligands within a small-molecule pocket created by the dimerization of STING.
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