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Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA.

<div class='caption-title'>(A) Chemical formula of DMXAA.</div>
<div class='caption-title'>(A) 293T cells were transfected with IFN-β reporter constructs and STING variants as indicated. At 12 hr after transfection, cells were stimulated with ascending concentrations of DMXAA. Luciferase activity was determined after another 12 hr. Shown are the means of triplicates + SEM, representative of three independent experiments.</div>
<div class='caption-title'>(A) 293T cells were transfected with reporter constructs and the indicated hSTING variants. At 12 hr after transfection, cells were stimulated with 0.18 mM DMXAA for another 12 hr, followed by luciferase assay. Shown are means of triplicates + SEM, representative of three independent experiments.</div>
Gao P, Zillinger T, Wang W, Ascano M, Dai P, Hartmann G, Tuschl T, Deng L, Barchet W, Patel DJ
OpenAccess logo Cell Rep 8 1668-1676 (2014)
Related entries: 4qxo, 4qxp, 4qxq

Cited: 48 times
EuropePMC logo PMID: 25199835

Abstract

The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) showed therapeutic promise against solid tumors in mouse models but subsequently failed in human clinical trials. DMXAA was later discovered to activate mouse, but not human, STING, an adaptor protein in the cyclic dinucleotide cGAMP-mediated signaling pathway, inducing type I interferon expression. To facilitate the development of compounds that target human STING, we combined structural, biophysical, and cellular assays to study mouse and human chimeric proteins and their interaction with DMXAA. We identified a single substitution (G230I) that enables a DMXAA-induced conformational transition of hSTING from an inactive "open" to an active "closed" state. We also identified a substitution within the binding pocket (Q266I) that cooperates with G230I and the previously identified S162A binding-pocket point substitution, rendering hSTING highly sensitive to DMXAA. These findings should facilitate the reciprocal engineering of DMXAA analogs that bind and stimulate wild-type hSTING and their exploitation for vaccine-adjuvant and anticancer drug development.

Reviews - 4qxr mentioned but not cited (1)

  1. Host-pathogen protein-nucleic acid interactions: A comprehensive review. Jain A, Mittal S, Tripathi LP, Nussinov R, Ahmad S. Comput Struct Biotechnol J 20 4415-4436 (2022)

Articles - 4qxr mentioned but not cited (3)

  1. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. Shang G, Zhang C, Chen ZJ, Bai XC, Zhang X. Nature 567 389-393 (2019)
  2. Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA. Gao P, Zillinger T, Wang W, Ascano M, Dai P, Hartmann G, Tuschl T, Deng L, Barchet W, Patel DJ. Cell Rep 8 1668-1676 (2014)
  3. Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA. Chang J, Hou S, Yan X, Li W, Xiao J. Molecules 28 2906 (2023)


Reviews citing this publication (18)

  1. Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA. Kato K, Omura H, Ishitani R, Nureki O. Annu Rev Biochem 86 541-566 (2017)
  2. Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response. Wan D, Jiang W, Hao J. Front Immunol 11 615 (2020)
  3. Translating nucleic acid-sensing pathways into therapies. Junt T, Barchet W. Nat Rev Immunol 15 529-544 (2015)
  4. Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway. Ding C, Song Z, Shen A, Chen T, Zhang A. Acta Pharm Sin B 10 2272-2298 (2020)
  5. Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy. Zheng J, Mo J, Zhu T, Zhuo W, Yi Y, Hu S, Yin J, Zhang W, Zhou H, Liu Z. Mol Cancer 19 133 (2020)
  6. Role of the cGAS-STING pathway in cancer development and oncotherapeutic approaches. Khoo LT, Chen LY. EMBO Rep 19 e46935 (2018)
  7. Myeloid neoplasms with germline DDX41 mutation. Cheah JJC, Hahn CN, Hiwase DK, Scott HS, Brown AL. Int J Hematol 106 163-174 (2017)
  8. Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy. Garland KM, Sheehy TL, Wilson JT. Chem Rev 122 5977-6039 (2022)
  9. The emerging roles of the STING adaptor protein in immunity and diseases. Liu X, Wang C. Immunology 147 285-291 (2016)
  10. Cytosolic sensing of aberrant DNA: arming STING on the endoplasmic reticulum. Wang Q, Liu X, Zhou Q, Wang C. Expert Opin Ther Targets 19 1397-1409 (2015)
  11. STING modulators: Predictive significance in drug discovery. Cui X, Zhang R, Cen S, Zhou J. Eur J Med Chem 182 111591 (2019)
  12. The emerging role of STING-dependent signaling on cell death. Sun F, Liu Z, Yang Z, Liu S, Guan W. Immunol Res 67 290-296 (2019)
  13. Regulation and function of the cGAS-MITA/STING axis in health and disease. Zhang ZD, Zhong B. Cell Insight 1 100001 (2022)
  14. cGAMP-activated cGAS-STING signaling: its bacterial origins and evolutionary adaptation by metazoans. Patel DJ, Yu Y, Xie W. Nat Struct Mol Biol 30 245-260 (2023)
  15. Pathophysiological Role of Nucleic Acid-Sensing Pattern Recognition Receptors in Inflammatory Diseases. Kano N, Ong GH, Ori D, Kawai T. Front Cell Infect Microbiol 12 910654 (2022)
  16. The Many Ways to Deal with STING. Coderch C, Arranz-Herrero J, Nistal-Villan E, de Pascual-Teresa B, Rius-Rocabert S. Int J Mol Sci 24 9032 (2023)
  17. The STING in Non-Alcoholic Fatty Liver Diseases: Potential Therapeutic Targets in Inflammation-Carcinogenesis Pathway. Lv J, Xing C, Chen Y, Bian H, Lv N, Wang Z, Liu M, Su L. Pharmaceuticals (Basel) 15 1241 (2022)
  18. Unlocking STING as a Therapeutic Antiviral Strategy. Paulis A, Tramontano E. Int J Mol Sci 24 7448 (2023)

Articles citing this publication (26)

  1. Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells. Tang CH, Zundell JA, Ranatunga S, Lin C, Nefedova Y, Del Valle JR, Hu CC. Cancer Res 76 2137-2152 (2016)
  2. Ancient Origin of cGAS-STING Reveals Mechanism of Universal 2',3' cGAMP Signaling. Kranzusch PJ, Wilson SC, Lee AS, Berger JM, Doudna JA, Vance RE. Mol Cell 59 891-903 (2015)
  3. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma. Thomsen MK, Skouboe MK, Boularan C, Vernejoul F, Lioux T, Leknes SL, Berthelsen MF, Riedel M, Cai H, Joseph JV, Perouzel E, Tiraby M, Vendelbo MH, Paludan SR. Oncogene 39 1652-1664 (2020)
  4. Dynamic Structural Differences between Human and Mouse STING Lead to Differing Sensitivity to DMXAA. Shih AY, Damm-Ganamet KL, Mirzadegan T. Biophys J 114 32-39 (2018)
  5. A novel transcript isoform of STING that sequesters cGAMP and dominantly inhibits innate nucleic acid sensing. Wang PH, Fung SY, Gao WW, Deng JJ, Cheng Y, Chaudhary V, Yuen KS, Ho TH, Chan CP, Zhang Y, Kok KH, Yang W, Chan CP, Jin DY. Nucleic Acids Res 46 4054-4071 (2018)
  6. OASes and STING: adaptive evolution in concert. Mozzi A, Pontremoli C, Forni D, Clerici M, Pozzoli U, Bresolin N, Cagliani R, Sironi M. Genome Biol Evol 7 1016-1032 (2015)
  7. STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. Skouboe MK, Knudsen A, Reinert LS, Boularan C, Lioux T, Perouzel E, Thomsen MK, Paludan SR. PLoS Pathog 14 e1006976 (2018)
  8. Activation of STING Signaling Pathway Effectively Blocks Human Coronavirus Infection. Liu W, Reyes HM, Yang JF, Li Y, Stewart KM, Basil MC, Lin SM, Katzen J, Morrisey EE, Weiss SR, You J. J Virol 95 e00490-21 (2021)
  9. Ligand-induced Ordering of the C-terminal Tail Primes STING for Phosphorylation by TBK1. Tsuchiya Y, Jounai N, Takeshita F, Ishii KJ, Mizuguchi K. EBioMedicine 9 87-96 (2016)
  10. Selective reactivation of STING signaling to target Merkel cell carcinoma. Liu W, Kim GB, Krump NA, Zhou Y, Riley JL, You J. Proc Natl Acad Sci U S A 117 13730-13739 (2020)
  11. Activation of cGAS-dependent antiviral responses by DNA intercalating agents. Pépin G, Nejad C, Thomas BJ, Ferrand J, McArthur K, Bardin PG, Williams BR, Gantier MP. Nucleic Acids Res 45 198-205 (2017)
  12. Rat and human STINGs profile similarly towards anticancer/antiviral compounds. Zhang H, Han MJ, Tao J, Ye ZY, Du XX, Deng MJ, Zhang XY, Li LF, Jiang ZF, Su XD. Sci Rep 5 18035 (2015)
  13. Combination of anti-vascular agent - DMXAA and HIF-1α inhibitor - digoxin inhibits the growth of melanoma tumors. Smolarczyk R, Cichoń T, Pilny E, Jarosz-Biej M, Poczkaj A, Kułach N, Szala S. Sci Rep 8 7355 (2018)
  14. Proteomic response to 5,6-dimethylxanthenone 4-acetic acid (DMXAA, vadimezan) in human non-small cell lung cancer A549 cells determined by the stable-isotope labeling by amino acids in cell culture (SILAC) approach. Pan ST, Zhou ZW, He ZX, Zhang X, Yang T, Yang YX, Wang D, Qiu JX, Zhou SF. Drug Des Devel Ther 9 937-968 (2015)
  15. Comparison of adjuvants to optimize influenza neutralizing antibody responses. Rudicell RS, Garinot M, Kanekiyo M, Kamp HD, Swanson K, Chou TH, Dai S, Bedel O, Simard D, Gillespie RA, Yang K, Reardon M, Avila LZ, Besev M, Dhal PK, Dharanipragada R, Zheng L, Duan X, Dinapoli J, Vogel TU, Kleanthous H, Mascola JR, Graham BS, Haensler J, Wei CJ, Nabel GJ. Vaccine 37 6208-6220 (2019)
  16. Design, synthesis, and biological evaluation of C7-functionalized DMXAA derivatives as potential human-STING agonists. Hwang J, Kang T, Lee J, Choi BS, Han S. Org Biomol Chem 17 1869-1874 (2019)
  17. G10 is a direct activator of human STING. Banerjee M, Middya S, Shrivastava R, Basu S, Ghosh R, Pryde DC, Yadav DB, Surya A. PLoS One 15 e0237743 (2020)
  18. Polymorphisms in STING Affect Human Innate Immune Responses to Poxviruses. Kennedy RB, Haralambieva IH, Ovsyannikova IG, Voigt EA, Larrabee BR, Schaid DJ, Zimmermann MT, Oberg AL, Poland GA. Front Immunol 11 567348 (2020)
  19. Cellular Target Deconvolution of Small Molecules Using a Selection-Based Genetic Screening Platform. Zhao J, Tang Z, Selvaraju M, Johnson KA, Douglas JT, Gao PF, Petrassi HM, Wang MZ, Wang J. ACS Cent Sci 8 1424-1434 (2022)
  20. Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner. Abraham J, Botto S, Mizuno N, Pryke K, Gall B, Boehm D, Sali TM, Jin H, Nilsen A, Gough M, Baird J, Chakhtoura M, Subra C, Trautmann L, Haddad EK, DeFilippis VR. Front Immunol 11 1430 (2020)
  21. Molecular Dynamics Simulations Reveal the Modulated Mechanism of STING Conformation. Chen L, Zhao S, Zhu Y, Liu Y, Li H, Zhao Q. Interdiscip Sci 13 751-765 (2021)
  22. Tuning the Innate Immune Response to Cyclic Dinucleotides by Using Atomic Mutagenesis. Li Y, Fin A, Rovira AR, Su Y, Dippel AB, Valderrama JA, Riestra AM, Nizet V, Hammond MC, Tor Y. Chembiochem 21 2595-2598 (2020)
  23. 10th anniversary of discovering cGAMP: synthesis and beyond. Chen C. Org Chem Front 10 1086-1098 (2023)
  24. Design, synthesis, and STING-agonistic activity of benzo[b]thiophene-2-carboxamide derivatives. Zhou R, Wang X, Zhang D, Zhan Z, Duan W. Mol Divers (2023)
  25. Differential Regulation of the STING Pathway in Human Papillomavirus-Positive and -Negative Head and Neck Cancers. Saulters EL, Kennedy PT, Carter RJ, Alsufyani A, Jones TM, Woolley JF, Dahal LN. Cancer Res Commun 4 118-133 (2024)
  26. Letter Unraveling the molecular details of the innate immune response. Fernández-Recio J. EBioMedicine 9 7-8 (2016)


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