Stimulator of interferon genes (STING) binds cyclic dinucleotides (CDNs), which induce a large conformational change of the protein. The structural basis of activation of STING by CDNs is rather well understood. Unliganded STING forms an open dimer that undergoes a large conformational change (∼10 Å) to a closed conformation upon the binding of a CDN molecule. This event activates downstream effectors of STING and subsequently leads to activation of the type 1 interferon response. However, a previously solved structure of STING with 3',3'-c-di-GMP shows Mg atoms mediating the interaction of STING with this CDN. Here, it is shown that no Mg atoms are needed for this interaction; in fact, magnesium can in some cases obstruct the binding of a CDN to STING.

Gilead Sciences Research Centre at IOCB Prague Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nam 2 166 10 Prague Czech Republic

See more in PubMed

Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L. W., Kapral, G. J., Grosse-Kunstleve, R. W., McCoy, A. J., Moriarty, N. W., Oeffner, R., Read, R. J., Richardson, D. C., Richardson, J. S., Terwilliger, T. C. & Zwart, P. H. (2010). Acta Cryst. D66, 213–221. PubMed PMC

Barber, G. N. (2015). Nature Rev. Immunol. 15, 760–770. PubMed PMC

Boura, E., Rezabkova, L., Brynda, J., Obsilova, V. & Obsil, T. (2010). Acta Cryst. D66, 1351–1357. PubMed

Chen, Q., Sun, L. & Chen, Z. J. (2016). Nature Immunol. 17, 1142–1149. PubMed

Corrales, L., Glickman, L. H., McWhirter, S. M., Kanne, D. B., Sivick, K. E., Katibah, G. E., Woo, S. R., Lemmens, E., Banda, T., Leong, J. J., Metchette, K., Dubensky, T. W. Jr & Gajewski, T. F. (2015). Cell. Rep. 11, 1018–1030. PubMed PMC

Debreczeni, J. É. & Emsley, P. (2012). Acta Cryst. D68, 425–430. PubMed PMC

Fitzgerald, K. A., McWhirter, S. M., Faia, K. L., Rowe, D. C., Latz, E., Golenbock, D. T., Coyle, A. J., Liao, S. M. & Maniatis, T. (2003). Nature Immunol. 4, 491–496. PubMed

Fu, J., Kanne, D. B., Leong, M., Glickman, L. H., McWhirter, S. M., Lemmens, E., Mechette, K., Leong, J. J., Lauer, P., Liu, W., Sivick, K. E., Zeng, Q., Soares, K. C., Zheng, L., Portnoy, D. A., Woodward, J. J., Pardoll, D. M., Dubensky, T. W. Jr & Kim, Y. (2015). Sci. Transl. Med. 7, 283ra52. PubMed PMC

Hercik, K., Brynda, J., Nencka, R. & Boura, E. (2017). Arch. Virol. 162, 2091–2096. PubMed

Huang, Y.-H., Liu, X.-Y., Du, X.-X., Jiang, Z.-F. & Su, X.-D. (2012). Nature Struct. Mol. Biol. 19, 728–730. PubMed

Kabsch, W. (2010). Acta Cryst. D66, 125–132. PubMed PMC

Leonarski, F., D’Ascenzo, L. & Auffinger, P. (2017). Nucleic Acids Res. 45, 987–1004. PubMed PMC

McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C. & Read, R. J. (2007). J. Appl. Cryst. 40, 658–674. PubMed PMC

Sato, M., Arakawa, T., Nam, Y.-W., Nishimoto, M., Kitaoka, M. & Fushinobu, S. (2015). Biochim. Biophys. Acta, 1854, 333–340. PubMed

Shang, G., Zhang, C., Chen, Z. J., Bai, X.-C. & Zhang, X. (2019). Nature (London), 567, 389–393. PubMed PMC

Shi, H., Wu, J., Chen, Z. J. & Chen, C. (2015). Proc. Natl Acad. Sci. USA, 112, 8947–8952. PubMed PMC

Shu, C., Yi, G., Watts, T., Kao, C. C. & Li, P. (2012). Nature Struct. Mol. Biol. 19, 722–724. PubMed PMC

Strzyz, P. (2019). Nature Rev. Mol. Cell Biol. 20, 266. PubMed

Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G., McCoy, A., McNicholas, S. J., Murshudov, G. N., Pannu, N. S., Potterton, E. A., Powell, H. R., Read, R. J., Vagin, A. & Wilson, K. S. (2011). Acta Cryst. D67, 235–242. PubMed PMC

Yin, Q., Tian, Y., Kabaleeswaran, V., Jiang, X., Tu, D., Eck, M. J., Chen, Z. J. & Wu, H. (2012). Mol. Cell, 46, 735–745. PubMed PMC

Zhang, C., Shang, G., Gui, X., Zhang, X., Bai, X.-C. & Chen, Z. J. (2019). Nature (London), 567, 394–398. PubMed PMC

Zhang, X., Shi, H. P., Wu, J. X., Zhang, X. W., Sun, L. J., Chen, C. & Chen, Z. J. J. (2013). Mol. Cell, 51, 226–235. PubMed PMC

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein