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

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Basic information

Entry
Database: PDB / ID: 4iwo
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 interferon-alpha production / positive regulation of type I interferon production / canonical NF-kappaB signal transduction / positive regulation of autophagy / negative regulation of TORC1 signaling / positive regulation of TORC1 signaling / TICAM1-dependent activation of IRF3/IRF7 / Regulation of innate immune responses to cytosolic DNA / activation of innate immune response / 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 / response to virus / DDX58/IFIH1-mediated induction of interferon-alpha/beta / 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 / protein kinase activity / defense response to Gram-positive bacterium / inflammatory response / negative regulation of gene expression / protein phosphorylation / intracellular membrane-bounded organelle / protein serine kinase activity / innate immune response / 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 / cytosol / cytoplasm
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-1H4 / Serine/threonine-protein kinase TBK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 2.61 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 1.1Apr 24, 2013Group: Non-polymer description
Revision 1.2May 22, 2013Group: Database references
Revision 1.3Feb 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)76,3712
Polymers75,9231
Non-polymers4491
Water905
1
A: Serine/threonine-protein kinase TBK1
hetero molecules

A: Serine/threonine-protein kinase TBK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,7434
Polymers151,8462
Non-polymers8972
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555y,x,-z1
Unit cell
Length a, b, c (Å)136.600, 136.600, 87.380
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: 75922.844 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-1H4 / N-{3-[(5-cyclopropyl-2-{[3-(2-oxopyrrolidin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]propyl}cyclobutanecarboxamide


Mass: 448.561 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H32N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O

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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: 3.1 Å3/Da / Density % sol: 60.32 %
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: 2.6→50 Å / Num. obs: 28196 / % possible obs: 96.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 97.63 Å2

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Processing

Software
NameVersionClassificationNB
PHENIX1.8.1_1168refinement
PDB_EXTRACT3.11data extraction
ADSCQuantumdata collection
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MIR / Resolution: 2.61→40.984 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.39 / σ(F): 1.99 / Phase error: 34.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2629 1409 5 %RANDOM
Rwork0.2448 ---
obs0.2457 28196 97.46 %-
all-29240 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 375.23 Å2 / Biso mean: 124.9266 Å2 / Biso min: 58.63 Å2
Refinement stepCycle: LAST / Resolution: 2.61→40.984 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5066 0 33 5 5104
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0035209
X-RAY DIFFRACTIONf_angle_d0.5787029
X-RAY DIFFRACTIONf_chiral_restr0.041780
X-RAY DIFFRACTIONf_plane_restr0.002894
X-RAY DIFFRACTIONf_dihedral_angle_d13.111954
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.6095-2.70280.39251380.36282623276197
2.7028-2.8110.39861420.323627072849100
2.811-2.93890.36061430.307827152858100
2.9389-3.09380.3431420.305326982840100
3.0938-3.28750.32931430.29752714285799
3.2875-3.54120.37251410.30882676281798
3.5412-3.89730.40941260.34932407253388
3.8973-4.46070.23651410.23092681282297
4.4607-5.61770.21911460.212727722918100
5.6177-40.98930.20771470.20192794294197
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.47050.32350.44151.58460.44362.3274-0.0264-0.27310.86550.3901-0.0852-0.0324-0.3272-0.15760.07240.9979-0.1309-0.15080.6711-0.03690.9857-27.3232-16.550518.8871
22.1415-0.66850.32651.9857-0.32292.5597-0.14620.08751.06010.04730.0040.8693-0.7418-0.46360.11820.9991-0.0852-0.14020.890.04441.3384-49.6212-17.71815.1714
31.86181.246-1.22882.1306-1.18970.5344-0.32570.2283-0.2221-0.28680.1572-0.02090.1176-0.27670.06430.9586-0.3636-0.08730.77310.07540.6948-44.695-53.8744-6.4337
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq -2:160)A-2 - 160
2X-RAY DIFFRACTION2chain 'A' and (resseq 161:294)A161 - 294
3X-RAY DIFFRACTION3chain 'A' and (resseq 295:657)A295 - 657

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