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- PDB-8ik3: Structure of Stimulator of interferon genes/ligand complex -

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Basic information

Entry
Database: PDB / ID: 8ik3
TitleStructure of Stimulator of interferon genes/ligand complex
ComponentsStimulator of interferon genes protein,Immune protein Tsi3
KeywordsIMMUNE SYSTEM / complex
Function / homology
Function and homology information


STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / 2',3'-cyclic GMP-AMP binding / proton channel activity / cyclic-di-GMP binding / STING mediated induction of host immune responses / IRF3-mediated induction of type I IFN / cGAS/STING signaling pathway / positive regulation of type I interferon-mediated signaling pathway ...STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / 2',3'-cyclic GMP-AMP binding / proton channel activity / cyclic-di-GMP binding / STING mediated induction of host immune responses / IRF3-mediated induction of type I IFN / cGAS/STING signaling pathway / positive regulation of type I interferon-mediated signaling pathway / reticulophagy / pattern recognition receptor signaling pathway / cellular response to exogenous dsRNA / cytoplasmic pattern recognition receptor signaling pathway / autophagosome membrane / antiviral innate immune response / positive regulation of macroautophagy / autophagosome assembly / cellular response to organic cyclic compound / positive regulation of type I interferon production / autophagosome / cellular response to interferon-beta / signaling adaptor activity / positive regulation of defense response to virus by host / Regulation of innate immune responses to cytosolic DNA / endoplasmic reticulum-Golgi intermediate compartment membrane / activation of innate immune response / positive regulation of interferon-beta production / secretory granule membrane / cytoplasmic vesicle membrane / peroxisome / positive regulation of DNA-binding transcription factor activity / SARS-CoV-1 activates/modulates innate immune responses / positive regulation of protein binding / protein complex oligomerization / regulation of inflammatory response / defense response to virus / mitochondrial outer membrane / RNA polymerase II-specific DNA-binding transcription factor binding / endosome / Golgi membrane / innate immune response / ubiquitin protein ligase binding / Neutrophil degranulation / endoplasmic reticulum membrane / protein kinase binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / perinuclear region of cytoplasm / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / metal ion binding / plasma membrane / cytosol
Similarity search - Function
: / Stimulator of interferon genes protein / Stimulator of interferon genes protein, C-terminal domain superfamily / Transmembrane protein 173 / Prokaryotic membrane lipoprotein lipid attachment site profile.
Similarity search - Domain/homology
cGAMP / Stimulator of interferon genes protein / Immune protein Tsi3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLu, D.F. / Shang, G.J.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2021YFC2301400 China
CitationJournal: Mol Cell / Year: 2023
Title: The mechanism of STING autoinhibition and activation.
Authors: Sheng Liu / Bo Yang / Yingxiang Hou / Kaige Cui / Xiaozhu Yang / Xiaoxiong Li / Lianwan Chen / Shichao Liu / Zhichao Zhang / Yuanyuan Jia / Yufeng Xie / Ying Xue / Xiaomei Li / Bingxue Yan / ...Authors: Sheng Liu / Bo Yang / Yingxiang Hou / Kaige Cui / Xiaozhu Yang / Xiaoxiong Li / Lianwan Chen / Shichao Liu / Zhichao Zhang / Yuanyuan Jia / Yufeng Xie / Ying Xue / Xiaomei Li / Bingxue Yan / Changxin Wu / Wen Deng / Jianxun Qi / Defen Lu / George F Gao / Peiyi Wang / Guijun Shang /
Abstract: 2',3'-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the ...2',3'-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the mechanism of STING activation. However, little is known about STING inhibition. Here, we found that apo-STING exhibits a bilayer with head-to-head as well as side-by-side packing, mediated by its ligand-binding domain (LBD). This type of assembly holds two endoplasmic reticulum (ER) membranes together not only to prevent STING ER exit but also to eliminate the recruitment of TBK1, representing the autoinhibited state of STING. Additionally, we obtained the filament structure of the STING/2',3'-cGAMP complex, which adopts a bent monolayer assembly mediated by LBD and transmembrane domain (TMD). The active, curved STING polymer could deform ER membrane to support its ER exit and anterograde transportation. Our data together provide a panoramic vision regarding STING autoinhibition and activation, which adds substantially to current understanding of the cGAS-STING pathway.
History
DepositionFeb 28, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 17, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Stimulator of interferon genes protein,Immune protein Tsi3
B: Stimulator of interferon genes protein,Immune protein Tsi3
C: Stimulator of interferon genes protein,Immune protein Tsi3
D: Stimulator of interferon genes protein,Immune protein Tsi3
E: Stimulator of interferon genes protein,Immune protein Tsi3
G: Stimulator of interferon genes protein,Immune protein Tsi3
F: Stimulator of interferon genes protein,Immune protein Tsi3
H: Stimulator of interferon genes protein,Immune protein Tsi3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)467,92212
Polymers465,2248
Non-polymers2,6984
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Stimulator of interferon genes protein,Immune protein Tsi3 / / hSTING / Endoplasmic reticulum interferon stimulator / ERIS / Mediator of IRF3 activation / hMITA / ...hSTING / Endoplasmic reticulum interferon stimulator / ERIS / Mediator of IRF3 activation / hMITA / Transmembrane protein 173 / Anti-toxin protein Tsi3


Mass: 58152.996 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STING1, ERIS, MITA, STING, TMEM173, tsi3, PA3485 / Production host: Homo sapiens (human) / References: UniProt: Q86WV6, UniProt: Q9HYC4
#2: Chemical
ChemComp-1SY / cGAMP / 2',3' cGAMP / c-GMP-AMP / c[G(2',5')pA(3',5')p] / Cyclic guanosine monophosphate–adenosine monophosphate


Mass: 674.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H24N10O13P2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: complex of stimulator of interferon genes and ligand / Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5 / Details: 20mM HEPES, 150 mM NaCl, 1mM DTT
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 216426 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00421431
ELECTRON MICROSCOPYf_angle_d0.58829179
ELECTRON MICROSCOPYf_dihedral_angle_d12.5592944
ELECTRON MICROSCOPYf_chiral_restr0.0393271
ELECTRON MICROSCOPYf_plane_restr0.0053683

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