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- EMDB-35504: Structure of Stimulator of interferon genes/ligand complex -

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Basic information

Entry
Database: EMDB / ID: EMD-35504
TitleStructure of Stimulator of interferon genes/ligand complex
Map data
Sample
  • Complex: complex of stimulator of interferon genes and ligand
    • Protein or peptide: Stimulator of interferon genes protein,Immune protein Tsi3
  • Ligand: cGAMPCyclic guanosine monophosphate–adenosine monophosphate
Keywordscomplex / IMMUNE SYSTEM
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 / autophagosome assembly / positive regulation of macroautophagy / cellular response to organic cyclic compound / autophagosome / positive regulation of type I interferon production / 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 / activation of innate immune response / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of interferon-beta production / secretory granule membrane / cytoplasmic vesicle membrane / peroxisome / SARS-CoV-1 activates/modulates innate immune responses / positive regulation of DNA-binding transcription factor activity / protein complex oligomerization / positive regulation of protein binding / 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
Stimulator of interferon genes protein / Immune protein Tsi3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLu DF / Shang GJ
Funding support China, 1 items
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, 2023-
Header (metadata) releaseMay 17, 2023-
Map releaseMay 17, 2023-
UpdateMay 1, 2024-
Current statusMay 1, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_35504.png

Downloads & links

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Map

FileDownload / File: emd_35504.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.69 Å
Density
Contour LevelBy AUTHOR: 0.27
Minimum - Maximum-1.2682766 - 2.0411317
Average (Standard dev.)0.015134421 (±0.06915369)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 198.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_35504_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_35504_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : complex of stimulator of interferon genes and ligand

EntireName: complex of stimulator of interferon genes and ligand
Components
  • Complex: complex of stimulator of interferon genes and ligand
    • Protein or peptide: Stimulator of interferon genes protein,Immune protein Tsi3
  • Ligand: cGAMPCyclic guanosine monophosphate–adenosine monophosphate

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Supramolecule #1: complex of stimulator of interferon genes and ligand

SupramoleculeName: complex of stimulator of interferon genes and ligand / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Stimulator of interferon genes protein,Immune protein Tsi3

MacromoleculeName: Stimulator of interferon genes protein,Immune protein Tsi3
type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.152996 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPHSSLHPSI PCPRGHGAQK AALVLLSACL VTLWGLGEPP EHTLRYLVLH LASLQLGLLL NGVCSLAEEL RHIHSRYRGS YWRTVRACL GCPLRRGALL LLSIYFYYSL PNAVGPPFTW MLALLGLSQA LNILLGLKGL APAEISAVCE KGNFNVAHGL A WSYYIGYL ...String:
MPHSSLHPSI PCPRGHGAQK AALVLLSACL VTLWGLGEPP EHTLRYLVLH LASLQLGLLL NGVCSLAEEL RHIHSRYRGS YWRTVRACL GCPLRRGALL LLSIYFYYSL PNAVGPPFTW MLALLGLSQA LNILLGLKGL APAEISAVCE KGNFNVAHGL A WSYYIGYL RLILPELQAR IRTYNQHYNN LLRGAVSQRL YILLPLDCGV PDNLSMADPN IRFLDKLPQQ TGDRAGIKDR VY SNSIYEL LENGQRAGTC VLEYATPLQT LFAMSQYSQA GFSREDRLEQ AKLFCRTLED ILADAPESQN NCRLIAYQEP ADD SSFSLS QEVLRHLRQE EKEEVTVGSL KTSAVPSTST MSQEPELLIS GMEKPLPLRT DFSLEVLFQG PVDFDKTLTH PNGL VVERP VGFDARRSAE GFRFDEGGKL RNPRQLEVQR QDAPPPPDLA SRRLGDGEAR YKVEEDDGGS AGSEYRLWAA KPAGA RWIV VSASEQSEDG EPTFALAWAL LERARLQSSH HHHHHHH

UniProtKB: Stimulator of interferon genes protein, Immune protein Tsi3

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Macromolecule #2: cGAMP

MacromoleculeName: cGAMP / type: ligand / ID: 2 / Number of copies: 4 / Formula: 1SY
Molecular weightTheoretical: 674.411 Da
Chemical component information

ChemComp-1SY:
cGAMP / Cyclic guanosine monophosphate–adenosine monophosphate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.5 / Details: 20mM HEPES, 150 mM NaCl, 1mM DTT
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4loh

Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 216426

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