دورية أكاديمية
أعرض في EDS

Activation of human STING by a molecular glue-like compound.

التفاصيل البيبلوغرافية
العنوان: Activation of human STING by a molecular glue-like compound.
المؤلفون: Li J; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Canham SM; Novartis Institutes for BioMedical Research, Cambridge, MA, USA. steve.canham@novartis.com., Wu H; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Henault M; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Chen L; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Liu G; Novartis Institutes for BioMedical Research, San Diego, CA, USA., Chen Y; Novartis Institutes for BioMedical Research, San Diego, CA, USA., Yu G; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Miller HR; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Hornak V; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Brittain SM; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Michaud GA; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Tutter A; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Broom W; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Digan ME; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., McWhirter SM; Aduro Biotech, Inc., Berkeley, CA, USA., Sivick KE; Aduro Biotech, Inc., Berkeley, CA, USA., Pham HT; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Chen CH; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Tria GS; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., McKenna JM; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Schirle M; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Mao X; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Nicholson TB; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Wang Y; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Jenkins JL; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Jain RK; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Tallarico JA; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Patel SJ; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Zheng L; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Ross NT; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Cho CY; Novartis Institutes for BioMedical Research, San Diego, CA, USA., Zhang X; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. xuewu.zhang@utsouthwestern.edu.; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA. xuewu.zhang@utsouthwestern.edu., Bai XC; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. xiaochen.bai@utsouthwestern.edu.; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. xiaochen.bai@utsouthwestern.edu., Feng Y; Novartis Institutes for BioMedical Research, Cambridge, MA, USA. yan.feng@novartis.com.
المصدر: Nature chemical biology [Nat Chem Biol] 2024 Mar; Vol. 20 (3), pp. 365-372. Date of Electronic Publication: 2023 Oct 12.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: New York, NY : Nature Pub. Group, [2005]-
مواضيع طبية MeSH: Adaptor Proteins, Signal Transducing*/metabolism , Membrane Proteins*/metabolism, Animals ; Humans ; Biological Assay ; Cytosol ; Immunity, Innate ; Ligands
مستخلص: Stimulator 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.
(© 2023. The Author(s).)
التعليقات: Comment in: Nat Rev Drug Discov. 2023 Dec;22(12):955. (PMID: 37907755)
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معلومات مُعتمدة: R01 CA273595 United States CA NCI NIH HHS; U24 GM129547 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Adaptor Proteins, Signal Transducing)
0 (Ligands)
0 (Membrane Proteins)
تواريخ الأحداث: Date Created: 20231012 Date Completed: 20240304 Latest Revision: 20240309
رمز التحديث: 20240309
مُعرف محوري في PubMed: PMC10907298
DOI: 10.1038/s41589-023-01434-y
PMID: 37828400
قاعدة البيانات: MEDLINE
الوصف
تدمد:1552-4469
DOI:10.1038/s41589-023-01434-y