Structure-function analysis of STING activation by c[G(2′,5′) pA(3′,5′)p] and targeting by antiviral DMXAA Journal Article
| Authors: | Gao, P.; Ascano, M.; Zillinger, T.; Wang, W.; Dai, P.; Serganov, A. A.; Gaffney, B. L.; Shuman, S.; Jones, R. A.; Deng, L.; Hartmann, G.; Barchet, W.; Tuschl, T.; Patel, D. J. |
| Article Title: | Structure-function analysis of STING activation by c[G(2′,5′) pA(3′,5′)p] and targeting by antiviral DMXAA |
| Abstract: | 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 hSTINGH232 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 mStingR231 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. © 2013 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; unclassified drug; interferon; nonhuman; protein conformation; protein analysis; animal cell; mouse; animals; mice; protein; membrane proteins; structure-activity relationship; cyclic amp; crystal structure; models, molecular; dimerization; crystallography, x-ray; protein structure; point mutation; mutagenesis; dinucleotide; antiviral agents; metazoa; cyclic gmp; interferon type i; isomer; vadimezan; xanthones; nucleotide binding site; interferon regulatory factor-3; sting protein; nucleotides, cyclic |
| Journal Title: | Cell |
| Volume: | 154 |
| Issue: | 4 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2013-08-15 |
| Start Page: | 748 |
| End Page: | 762 |
| Language: | English |
| DOI: | 10.1016/j.cell.2013.07.023 |
| PROVIDER: | scopus |
| PUBMED: | 23910378 |
| PMCID: | PMC4386733 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 1 October 2013" - "CODEN: CELLB" - "Source: Scopus" |
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