Activation of STING by targeting a pocket in the transmembrane domain

Defen Lu, Guijun Shang, Jie Li, Yong Lu, Xiao-chen Bai () and Xuewu Zhang ()
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Defen Lu: University of Texas Southwestern Medical Center
Guijun Shang: University of Texas Southwestern Medical Center
Jie Li: University of Texas Southwestern Medical Center
Yong Lu: University of Texas Southwestern Medical Center
Xiao-chen Bai: University of Texas Southwestern Medical Center
Xuewu Zhang: University of Texas Southwestern Medical Center

Nature, 2022, vol. 604, issue 7906, 557-562

Abstract: Abstract Stimulator of interferon genes (STING) is an adaptor protein in innate immunity against DNA viruses or bacteria1–5. 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 bacteria1,6,7. 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 pathways8,9. 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)10, 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.

Date: 2022
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DOI: 10.1038/s41586-022-04559-7

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