- PDB-7sii: Human STING bound to both cGAMP and 1-[(2-chloro-6-fluorophenyl)m... -
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Basic information
Entry
Database: PDB / ID: 7sii
Title
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)
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35GM130289
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM143158
United States
Cancer Prevention and Research Institute of Texas (CPRIT)
RP160082
United States
Cancer Prevention and Research Institute of Texas (CPRIT)
RP170644
United States
Citation
Journal: Nature / Year: 2022 Title: Activation of STING by targeting a pocket in the transmembrane domain. Authors: Defen Lu / Guijun Shang / Jie Li / Yong Lu / Xiao-Chen Bai / Xuewu Zhang / 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 ...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.
A: Stimulator of interferon genes protein B: Stimulator of interferon genes protein C: Stimulator of interferon genes protein D: Stimulator of interferon genes protein hetero molecules
Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Vitrification
Cryogen name: NITROGEN
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Electron microscopy imaging
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
Microscopy
Model: FEI TITAN KRIOS
Electron gun
Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lens
Mode: BRIGHT FIELD
Image recording
Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
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Processing
Software
Name
Version
Classification
phenix.real_space_refine
1.19.2_4158
refinement
PHENIX
1.19.2_4158
refinement
EM software
Name: RELION / Version: 3.1 / Category: 3D reconstruction
CTF correction
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Symmetry
Point symmetry: C2 (2 fold cyclic)
3D reconstruction
Resolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 231556 / Algorithm: FOURIER SPACE / Num. of class averages: 4 / Symmetry type: POINT
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