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- EMDB-0502: Cryo-EM structure of full-length human STING in the apo state -

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Basic information

Entry
Database: EMDB / ID: EMD-0502
TitleCryo-EM structure of full-length human STING in the apo state
Map dataFull-length human STING in the apo state
Sample
  • Complex: full-length human STING
    • Protein or peptide: Stimulator of interferon protein
KeywordsER / membrane / adaptor / IMMUNE SYSTEM
Function / homology
Function and homology information


STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / proton channel activity / 2',3'-cyclic GMP-AMP binding / cyclic-di-GMP binding / STING mediated induction of host immune responses / cGAS/STING signaling pathway / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway ...STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / proton channel activity / 2',3'-cyclic GMP-AMP binding / cyclic-di-GMP binding / STING mediated induction of host immune responses / cGAS/STING signaling pathway / IRF3-mediated induction of type I IFN / 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 / 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 / positive regulation of interferon-beta production / activation of innate immune response / endoplasmic reticulum-Golgi intermediate compartment membrane / 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 / cytoplasmic vesicle / defense response to virus / mitochondrial outer membrane / RNA polymerase II-specific DNA-binding transcription factor binding / endosome / Golgi membrane / nucleotide binding / 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 / plasma membrane / cytosol
Similarity search - Function
: / Stimulator of interferon genes protein / Stimulator of interferon genes protein, C-terminal domain superfamily / Transmembrane protein 173
Similarity search - Domain/homology
Stimulator of interferon genes protein / Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsShang G / Zhang C
Funding support United States, 6 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM088197 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM130289 United States
Howard Hughes Medical Institute (HHMI) United States
Welch FoundationI-1389 United States
Welch FoundationI-1702 United States
Welch FoundationI-1944 United States
CitationJournal: Nature / Year: 2019
Title: Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP.
Authors: Guijun Shang / Conggang Zhang / Zhijian J Chen / Xiao-Chen Bai / Xuewu Zhang /
Abstract: Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP-AMP synthase, which produces 2'3'-cyclic GMP-AMP (cGAMP) that binds ...Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP-AMP synthase, which produces 2'3'-cyclic GMP-AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS). STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP. However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.
History
DepositionJan 28, 2019-
Header (metadata) releaseMar 6, 2019-
Map releaseMar 6, 2019-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0233
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0233
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6nt5
  • Surface level: 0.0233
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0502.png

Downloads & links

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Map

FileDownload / File: emd_0502.map.gz / Format: CCP4 / Size: 35.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull-length human STING in the apo state
Voxel sizeX=Y=Z: 0.84 Å
Density
Contour LevelBy AUTHOR: 0.0233 / Movie #1: 0.0233
Minimum - Maximum-0.030996079 - 0.07230262
Average (Standard dev.)0.00025128003 (±0.0032912088)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions210210210
Spacing210210210
CellA=B=C: 176.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.840.840.84
M x/y/z210210210
origin x/y/z0.0000.0000.000
length x/y/z176.400176.400176.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS210210210
D min/max/mean-0.0310.0720.000

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Supplemental data

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Sample components

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Entire : full-length human STING

EntireName: full-length human STING
Components
  • Complex: full-length human STING
    • Protein or peptide: Stimulator of interferon protein

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Supramolecule #1: full-length human STING

SupramoleculeName: full-length human STING / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Stimulator of interferon protein

MacromoleculeName: Stimulator of interferon protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.985379 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 DFSLEVLFQ

UniProtKB: Stimulator of interferon genes protein

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.5 mg/mL
BufferpH: 8
GridPretreatment - Type: GLOW DISCHARGE / Details: unspecified
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
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Stochastic Gradient Descent
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 75479
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-6nt5:
Cryo-EM structure of full-length human STING in the apo state

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