7SII
Human STING bound to both cGAMP and 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide (Compound 53)
Summary for 7SII
| Entry DOI | 10.2210/pdb7sii/pdb |
| EMDB information | 25142 |
| Descriptor | Stimulator of interferon genes protein, 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide, cGAMP (3 entities in total) |
| Functional Keywords | sting, agonist, activate conformation, oligomer, immune system |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 160544.17 |
| Authors | |
| Primary citation | Lu, D.,Shang, G.,Li, J.,Lu, Y.,Bai, X.C.,Zhang, X. Activation of STING by targeting a pocket in the transmembrane domain. Nature, 604:557-562, 2022 Cited by PubMed Abstract: Stimulator of interferon genes (STING) is an adaptor protein in innate immunity against DNA viruses or bacteria. STING-mediated immunity could be exploited in the development of vaccines or cancer immunotherapies. STING is a transmembrane dimeric protein that is located in the endoplasmic reticulum or in the Golgi apparatus. STING is activated by the binding of its cytoplasmic ligand-binding domain to cyclic dinucleotides that are produced by the DNA sensor cyclic GMP-AMP (cGAMP) synthase or by invading bacteria. Cyclic dinucleotides induce a conformational change in the STING ligand-binding domain, which leads to a high-order oligomerization of STING that is essential for triggering the downstream signalling pathways. However, the cGAMP-induced STING oligomers tend to dissociate in solution and have not been resolved to high resolution, which limits our understanding of the activation mechanism. Here we show that a small-molecule agonist, compound 53 (C53), promotes the oligomerization and activation of human STING through a mechanism orthogonal to that of cGAMP. We determined a cryo-electron microscopy structure of STING bound to both C53 and cGAMP, revealing a stable oligomer that is formed by side-by-side packing and has a curled overall shape. Notably, C53 binds to a cryptic pocket in the STING transmembrane domain, between the two subunits of the STING dimer. This binding triggers outward shifts of transmembrane helices in the dimer, and induces inter-dimer interactions between these helices to mediate the formation of the high-order oligomer. Our functional analyses show that cGAMP and C53 together induce stronger activation of STING than either ligand alone. PubMed: 35388221DOI: 10.1038/s41586-022-04559-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.45 Å) |
Structure validation
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