8FLM

Cryo-EM structure of STING oligomer bound to cGAMP, NVS-STG2 and C53

Summary for 8FLM

• Entry DOI: 10.2210/pdb8flm/pdb
• EMDB information: 29281 29282
• Descriptor: Stimulator of interferon genes protein, 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid, cGAMP, ... (4 entities in total)
• Functional Keywords: sting, innate immunity, molecular glue, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 161399.23

Authors

Li, J.,Canham, S.M.,Zhang, X.,Bai, X.,Feng, Y. (deposition date: 2022-12-21, release date: 2023-11-01, Last modification date: 2024-03-13)

Primary citation

Li, J.,Canham, S.M.,Wu, H.,Henault, M.,Chen, L.,Liu, G.,Chen, Y.,Yu, G.,Miller, H.R.,Hornak, V.,Brittain, S.M.,Michaud, G.A.,Tutter, A.,Broom, W.,Digan, M.E.,McWhirter, S.M.,Sivick, K.E.,Pham, H.T.,Chen, C.H.,Tria, G.S.,McKenna, J.M.,Schirle, M.,Mao, X.,Nicholson, T.B.,Wang, Y.,Jenkins, J.L.,Jain, R.K.,Tallarico, J.A.,Patel, S.J.,Zheng, L.,Ross, N.T.,Cho, C.Y.,Zhang, X.,Bai, X.C.,Feng, Y.
Activation of human STING by a molecular glue-like compound.
Nat.Chem.Biol., 20:365-372, 2024

PubMed Abstract: 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.

PubMed: 37828400
DOI: 10.1038/s41589-023-01434-y

Experimental method

ELECTRON MICROSCOPY (2.9 Å)