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- EMDB-0506: Cryo-EM structure of the complex between human TBK1 and chicken STING -

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Basic information

Entry
Database: EMDB / ID: EMD-0506
TitleCryo-EM structure of the complex between human TBK1 and chicken STING
Map dataprimary map
Sample
  • Complex: full-length chicken STING and human TBK1
    • Complex: STING
      • Protein or peptide: Stimulator of interferon genes protein
    • Complex: TBK1
      • Protein or peptide: Serine/threonine-protein kinase TBK1
KeywordsER / kinase / adaptor / IMMUNE SYSTEM
Function / homology
Function and homology information


STING mediated induction of host immune responses / IRF3 mediated activation of type 1 IFN / STAT6-mediated induction of chemokines / positive regulation of xenophagy / serine/threonine protein kinase complex / proton channel activity / 2',3'-cyclic GMP-AMP binding / regulation of type I interferon production / dendritic cell proliferation / cyclic-di-GMP binding ...STING mediated induction of host immune responses / IRF3 mediated activation of type 1 IFN / STAT6-mediated induction of chemokines / positive regulation of xenophagy / serine/threonine protein kinase complex / proton channel activity / 2',3'-cyclic GMP-AMP binding / regulation of type I interferon production / dendritic cell proliferation / cyclic-di-GMP binding / cGAS/STING signaling pathway / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway / reticulophagy / Interleukin-37 signaling / TNFR1-induced proapoptotic signaling / TRAF6 mediated IRF7 activation / cytoplasmic pattern recognition receptor signaling pathway / type I interferon-mediated signaling pathway / autophagosome membrane / positive regulation of interferon-alpha production / antiviral innate immune response / positive regulation of macroautophagy / autophagosome assembly / positive regulation of type I interferon production / autophagosome / canonical NF-kappaB signal transduction / positive regulation of autophagy / negative regulation of TORC1 signaling / TICAM1-dependent activation of IRF3/IRF7 / positive regulation of TORC1 signaling / Regulation of innate immune responses to cytosolic DNA / activation of innate immune response / positive regulation of interferon-beta production / endoplasmic reticulum-Golgi intermediate compartment membrane / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Negative regulators of DDX58/IFIH1 signaling / Neutrophil degranulation / Regulation of TNFR1 signaling / phosphoprotein binding / peptidyl-threonine phosphorylation / response to virus / DDX58/IFIH1-mediated induction of interferon-alpha/beta / SARS-CoV-1 activates/modulates innate immune responses / protein complex oligomerization / positive regulation of peptidyl-serine phosphorylation / TRAF3-dependent IRF activation pathway / cytoplasmic vesicle / defense response to virus / protein phosphatase binding / peptidyl-serine phosphorylation / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / nucleic acid binding / non-specific serine/threonine protein kinase / protein kinase activity / defense response to Gram-positive bacterium / inflammatory response / Golgi membrane / negative regulation of gene expression / protein phosphorylation / innate immune response / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / endoplasmic reticulum membrane / 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 / ATP binding / identical protein binding / cytosol / cytoplasm
Similarity search - Function
TANK binding kinase 1, ubiquitin-like domain / TANK-binding kinase 1, coiled-coil domain 1 / TANK-binding kinase 1 coiled-coil domain 1 / TANK binding kinase 1 ubiquitin-like domain / : / Stimulator of interferon genes protein / Stimulator of interferon genes protein, C-terminal domain superfamily / Transmembrane protein 173 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...TANK binding kinase 1, ubiquitin-like domain / TANK-binding kinase 1, coiled-coil domain 1 / TANK-binding kinase 1 coiled-coil domain 1 / TANK binding kinase 1 ubiquitin-like domain / : / Stimulator of interferon genes protein / Stimulator of interferon genes protein, C-terminal domain superfamily / Transmembrane protein 173 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Stimulator of interferon genes protein / Stimulator of interferon genes protein / Serine/threonine-protein kinase TBK1
Similarity search - Component
Biological speciesGallus gallus (chicken) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 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: Structural basis of STING binding with and phosphorylation by TBK1.
Authors: Conggang Zhang / Guijun Shang / Xiang Gui / Xuewu Zhang / Xiao-Chen Bai / Zhijian J Chen /
Abstract: The invasion of mammalian cytoplasm by microbial DNA from infectious pathogens or by self DNA from the nucleus or mitochondria represents a danger signal that alerts the host immune system. Cyclic ...The invasion of mammalian cytoplasm by microbial DNA from infectious pathogens or by self DNA from the nucleus or mitochondria represents a danger signal that alerts the host immune system. Cyclic GMP-AMP synthase (cGAS) is a sensor of cytoplasmic DNA that activates the type-I interferon pathway. On binding to DNA, cGAS is activated to catalyse the synthesis of cyclic GMP-AMP (cGAMP) from GTP and ATP. cGAMP functions as a second messenger that binds to and activates stimulator of interferon genes (STING). STING then recruits and activates tank-binding kinase 1 (TBK1), which phosphorylates STING and the transcription factor IRF3 to induce type-I interferons and other cytokines. However, how cGAMP-bound STING activates TBK1 and IRF3 is not understood. Here we present the cryo-electron microscopy structure of human TBK1 in complex with cGAMP-bound, full-length chicken STING. The structure reveals that the C-terminal tail of STING adopts a β-strand-like conformation and inserts into a groove between the kinase domain of one TBK1 subunit and the scaffold and dimerization domain of the second subunit in the TBK1 dimer. In this binding mode, the phosphorylation site Ser366 in the STING tail cannot reach the kinase-domain active site of bound TBK1, which suggests that STING phosphorylation by TBK1 requires the oligomerization of both proteins. Mutational analyses validate the interaction mode between TBK1 and STING and support a model in which high-order oligomerization of STING and TBK1, induced by cGAMP, leads to STING phosphorylation by TBK1.
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: 0.048
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.048
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6nt9
  • Surface level: 0.048
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0506.png

Downloads & links

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Map

FileDownload / File: emd_0506.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationprimary map
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.048 / Movie #1: 0.048
Minimum - Maximum-0.21360976 - 0.3472147
Average (Standard dev.)0.00058755354 (±0.009017996)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 235.40001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z220220220
origin x/y/z0.0000.0000.000
length x/y/z235.400235.400235.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS220220220
D min/max/mean-0.2140.3470.001

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Supplemental data

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Sample components

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Entire : full-length chicken STING and human TBK1

EntireName: full-length chicken STING and human TBK1
Components
  • Complex: full-length chicken STING and human TBK1
    • Complex: STING
      • Protein or peptide: Stimulator of interferon genes protein
    • Complex: TBK1
      • Protein or peptide: Serine/threonine-protein kinase TBK1

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Supramolecule #1: full-length chicken STING and human TBK1

SupramoleculeName: full-length chicken STING and human TBK1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: STING

SupramoleculeName: STING / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Gallus gallus (chicken)

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Supramolecule #3: TBK1

SupramoleculeName: TBK1 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Serine/threonine-protein kinase TBK1

MacromoleculeName: Serine/threonine-protein kinase TBK1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 85.316695 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQSTSNHLWL LSDILGQGAT ANVFRGRHKK TGDLFAIKVF NNISFLRPVD VQMREFEVLK KLNHKNIVKL FAIEEETTTR HKVLIMEFC PCGSLYTVLE EPSNAYGLPE SEFLIVLRDV VGGMNHLREN GIVHRNIKPG NIMRVIGEDG QSVYKLTDFG A ARELEDDE ...String:
MQSTSNHLWL LSDILGQGAT ANVFRGRHKK TGDLFAIKVF NNISFLRPVD VQMREFEVLK KLNHKNIVKL FAIEEETTTR HKVLIMEFC PCGSLYTVLE EPSNAYGLPE SEFLIVLRDV VGGMNHLREN GIVHRNIKPG NIMRVIGEDG QSVYKLTDFG A ARELEDDE QFVSLYGTEE YLHPDMYERA VLRKDHQKKY GATVDLWSIG VTFYHAATGS LPFRPFEGPR RNKEVMYKII TG KPSGAIS GVQKAENGPI DWSGDMPVSC SLSRGLQVLL TPVLANILEA DQEKCWGFDQ FFAETSDILH RMVIHVFSLQ QMT AHKIYI HSYNTATIFH ELVYKQTKII SSNQELIYEG RRLVLEPGRL AQHFPKTTEE NPIFVVSREP LNTIGLIYEK ISLP KVHPR YDLDGDASMA KAITGVVCYA CRIASTLLLY QELMRKGIRW LIELIKDDYN ETVHKKTEVV ITLDFCIRNI EKTVK VYEK LMKINLEAAE LGEISDIHTK LLRLSSSQGT IETSLQDIDS RLSPGGSLAD AWAHQEGTHP KDRNVEKLQV LLNCMT EIY YQFKKDKAER RLAYNEEQIH KFDKQKLYYH ATKAMTHFTD ECVKKYEAFL NKSEEWIRKM LHLRKQLLSL TNQCFDI EE EVSKYQEYTN ELQETLPQKM FTASSGIKHT MTPIYPSSNT LVEMTLGMKK LKEEMEGVVK ELAENNHILE RFGSLTMD G GLRNVDCLGI HRPDYKDDDD K

UniProtKB: Serine/threonine-protein kinase TBK1

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Macromolecule #2: Stimulator of interferon genes protein

MacromoleculeName: Stimulator of interferon genes protein / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Gallus gallus (chicken)
Molecular weightTheoretical: 44.20707 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPQDPSTRSS PARLLIPEPR AGRARHAACV LLAVCFVVLF LSGEPLAPII RSVCTQLAAL QLGVLLKGCC CLAEEIFHLH SRHHGSLWQ VLCSCFPPRW YLALLLVGGS AYLDPPEDNG HSPRLALTLS CLCQLLVLAL GLQKLSAVEV SELTESSKKN V AHGLAWSY ...String:
MPQDPSTRSS PARLLIPEPR AGRARHAACV LLAVCFVVLF LSGEPLAPII RSVCTQLAAL QLGVLLKGCC CLAEEIFHLH SRHHGSLWQ VLCSCFPPRW YLALLLVGGS AYLDPPEDNG HSPRLALTLS CLCQLLVLAL GLQKLSAVEV SELTESSKKN V AHGLAWSY YIGYLKVVLP RLKECMEELS RTNPMLRAHR DTWKLHILVP LGCDIWDDLE KADSNIQYLA DLPETILTRA GI KRRVYKH SLYVIRDKDN KLRPCVLEFA SPLQTLCAMS QDDCAAFSRE QRLEQARLFY RSLRDILGSS KECAGLYRLI AYE EPAEPE SHFLSGLILW HLQQQQREEY MVQEELPLGT SSVELSLQVS SSDLPQPLRS DCPGIHRPDY KDDDDK

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: 48.0 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: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 86276
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

4im0


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-6nt9:
Cryo-EM structure of the complex between human TBK1 and chicken STING

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