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 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.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Gao
authors.forename: Manuel
authors.initials: M
authors.lastname: Ascano
authors.forename: Thomas
authors.initials: T
authors.lastname: Zillinger
authors.forename: Weiyi
authors.initials: W
authors.lastname: Wang
authors.forename: Peihong
authors.initials: P
authors.lastname: Dai
authors.forename: Artem A
authors.initials: AA
authors.lastname: Serganov
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Gaffney
authors.forename: Stewart
authors.initials: S
authors.lastname: Shuman
authors.forename: Roger A
authors.initials: RA
authors.lastname: Jones
authors.forename: Liang
authors.initials: L
authors.lastname: Deng
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D016296:Mutagenesis; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D011487:Protein Conformation; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000494:pharmacology*; D000099197:STING Protein
chemical_list: D000998:Antiviral Agents; D006152:Cyclic GMP; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D044004:Xanthones; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C066668:vadimezan
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