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Cryo-EM structure of STING oligomer bound to cGAMP, NVS-STG2 and C53Cryo-EM structure of STING oligomer bound to cGAMP, NVS-STG2 and C53
Structural highlights
FunctionSTING_HUMAN Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedStimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models. Activation of human STING by a molecular glue-like compound.,Li J, Canham SM, Wu H, Henault M, Chen L, Liu G, Chen Y, Yu G, Miller HR, Hornak V, Brittain SM, Michaud GA, Tutter A, Broom W, Digan ME, McWhirter SM, Sivick KE, Pham HT, Chen CH, Tria GS, McKenna JM, Schirle M, Mao X, Nicholson TB, Wang Y, Jenkins JL, Jain RK, Tallarico JA, Patel SJ, Zheng L, Ross NT, Cho CY, Zhang X, Bai XC, Feng Y Nat Chem Biol. 2023 Oct 12. doi: 10.1038/s41589-023-01434-y. PMID:37828400[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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