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- PDB-4iwp: Crystal structure and mechanism of activation of TBK1 -

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Basic information

Entry
Database: PDB / ID: 4iwp
TitleCrystal structure and mechanism of activation of TBK1
ComponentsSerine/threonine-protein kinase TBK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / ATP binding / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


IRF3 mediated activation of type 1 IFN / STAT6-mediated induction of chemokines / positive regulation of xenophagy / serine/threonine protein kinase complex / dendritic cell proliferation / regulation of type I interferon production / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway / Interleukin-37 signaling / cGAS/STING signaling pathway ...IRF3 mediated activation of type 1 IFN / STAT6-mediated induction of chemokines / positive regulation of xenophagy / serine/threonine protein kinase complex / dendritic cell proliferation / regulation of type I interferon production / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway / Interleukin-37 signaling / cGAS/STING signaling pathway / TNFR1-induced proapoptotic signaling / toll-like receptor 4 signaling pathway / TRAF6 mediated IRF7 activation / cytoplasmic pattern recognition receptor signaling pathway / type I interferon-mediated signaling pathway / antiviral innate immune response / positive regulation of macroautophagy / positive regulation of type I interferon production / canonical NF-kappaB signal transduction / positive regulation of interferon-alpha production / positive regulation of autophagy / negative regulation of TORC1 signaling / positive regulation of TORC1 signaling / TICAM1-dependent activation of IRF3/IRF7 / activation of innate immune response / Regulation of innate immune responses to cytosolic DNA / positive regulation of interferon-beta production / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Negative regulators of DDX58/IFIH1 signaling / phosphoprotein binding / Regulation of TNFR1 signaling / peptidyl-threonine phosphorylation / DDX58/IFIH1-mediated induction of interferon-alpha/beta / response to virus / SARS-CoV-1 activates/modulates innate immune responses / positive regulation of peptidyl-serine phosphorylation / TRAF3-dependent IRF activation pathway / peptidyl-serine phosphorylation / protein phosphatase binding / positive regulation of canonical NF-kappaB signal transduction / defense response to virus / Potential therapeutics for SARS / nucleic acid binding / non-specific serine/threonine protein kinase / defense response to Gram-positive bacterium / protein kinase activity / inflammatory response / protein phosphorylation / negative regulation of gene expression / intracellular membrane-bounded organelle / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / SARS-CoV-2 activates/modulates innate and adaptive immune responses / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Substrate Binding Domain Of Dnak; Chain:A; Domain 2 - #420 / 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 / Substrate Binding Domain Of Dnak; Chain:A; Domain 2 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Ubiquitin-like (UB roll) / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...Substrate Binding Domain Of Dnak; Chain:A; Domain 2 - #420 / 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 / Substrate Binding Domain Of Dnak; Chain:A; Domain 2 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Ubiquitin-like (UB roll) / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Roll / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Up-down Bundle / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-BX7 / Serine/threonine-protein kinase TBK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.065 Å
AuthorsPanne, D. / Larabi, A.
CitationJournal: Cell Rep / Year: 2013
Title: Crystal structure and mechanism of activation of TANK-binding kinase 1.
Authors: Larabi, A. / Devos, J.M. / Ng, S.L. / Nanao, M.H. / Round, A. / Maniatis, T. / Panne, D.
History
DepositionJan 24, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2013Provider: repository / Type: Initial release
Revision 1.1May 22, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase TBK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4572
Polymers75,8661
Non-polymers5911
Water00
1
A: Serine/threonine-protein kinase TBK1
hetero molecules

A: Serine/threonine-protein kinase TBK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,9154
Polymers151,7322
Non-polymers1,1832
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555y,x,-z1
Buried area4050 Å2
ΔGint-1 kcal/mol
Surface area62340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)135.410, 135.410, 86.360
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Serine/threonine-protein kinase TBK1 / NF-kappa-B-activating kinase / T2K / TANK-binding kinase 1


Mass: 75865.797 Da / Num. of mol.: 1 / Mutation: S172A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAK, TBK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UHD2, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-BX7 / N-(3-{[5-iodo-4-({3-[(thiophen-2-ylcarbonyl)amino]propyl}amino)pyrimidin-2-yl]amino}phenyl)pyrrolidine-1-carboxamide


Mass: 591.468 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26IN7O2S

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.01 Å3/Da / Density % sol: 59.17 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 5% PEG6000, pH 7.5, vapor diffusion, hanging drop, temperature 294K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 1.28 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 16, 2011
RadiationMonochromator: Diamond (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.28 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. all: 17481 / Num. obs: 17416 / % possible obs: 99.6 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 105.42 Å2

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Processing

Software
NameVersionClassificationNB
PHENIX1.8.1_1168refinement
PDB_EXTRACT3.11data extraction
ADSCQuantumdata collection
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.065→48.51 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.637 / SU ML: 0.59 / σ(F): 2 / Phase error: 40.71 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3346 871 5 %RANDOM
Rwork0.2798 ---
obs0.2826 17412 99.63 %-
all-17481 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 400 Å2 / Biso mean: 123.8828 Å2 / Biso min: 42.34 Å2
Refinement stepCycle: LAST / Resolution: 3.065→48.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5062 0 34 0 5096
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0025203
X-RAY DIFFRACTIONf_angle_d0.5097025
X-RAY DIFFRACTIONf_chiral_restr0.036778
X-RAY DIFFRACTIONf_plane_restr0.002895
X-RAY DIFFRACTIONf_dihedral_angle_d11.861961
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.0653-3.25730.44191410.3712681282298
3.2573-3.50870.44021440.338927302874100
3.5087-3.86170.37611430.317927302873100
3.8617-4.42020.34871460.292727592905100
4.4202-5.56770.33611450.280427622907100
5.5677-48.51590.28461520.241728793031100

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