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- PDB-6rsr: TBK1 in complex with compound 2 -

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Basic information

Entry
Database: PDB / ID: 6rsr
TitleTBK1 in complex with compound 2
ComponentsSerine/threonine-protein kinase TBK1
KeywordsIMMUNE SYSTEM / kinase / innate immunity / small molecule inhibitor
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 / regulation of type I interferon production / dendritic cell proliferation / cGAS/STING signaling pathway / IRF3-mediated induction of type I IFN / Interleukin-37 signaling / positive regulation of type I interferon-mediated signaling pathway ...IRF3 mediated activation of type 1 IFN / STAT6-mediated induction of chemokines / positive regulation of xenophagy / serine/threonine protein kinase complex / regulation of type I interferon production / dendritic cell proliferation / cGAS/STING signaling pathway / IRF3-mediated induction of type I IFN / Interleukin-37 signaling / positive regulation of type I interferon-mediated signaling pathway / cytoplasmic pattern recognition receptor signaling pathway / TNFR1-induced proapoptotic signaling / TRAF6 mediated IRF7 activation / toll-like receptor 4 signaling pathway / type I interferon-mediated signaling pathway / positive regulation of interferon-alpha production / positive regulation of type I interferon production / positive regulation of macroautophagy / canonical NF-kappaB signal transduction / positive regulation of autophagy / activation of innate immune response / antiviral innate immune response / negative regulation of TORC1 signaling / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / TICAM1-dependent activation of IRF3/IRF7 / positive regulation of interferon-beta production / positive regulation of TORC1 signaling / Regulation of innate immune responses to cytosolic DNA / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / PINK1-PRKN Mediated Mitophagy / Negative regulators of DDX58/IFIH1 signaling / peptidyl-threonine phosphorylation / phosphoprotein binding / Regulation of TNFR1 signaling / 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 / defense response to virus / 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 / 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 / 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 ...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-KHT / Serine/threonine-protein kinase TBK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.15 Å
AuthorsPanne, D. / Hillig, R.C. / Rengachari, S.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of BAY-985, a Highly Selective TBK1/IKK epsilon Inhibitor.
Authors: Lefranc, J. / Schulze, V.K. / Hillig, R.C. / Briem, H. / Prinz, F. / Mengel, A. / Heinrich, T. / Balint, J. / Rengachari, S. / Irlbacher, H. / Stockigt, D. / Bomer, U. / Bader, B. / Gradl, S. ...Authors: Lefranc, J. / Schulze, V.K. / Hillig, R.C. / Briem, H. / Prinz, F. / Mengel, A. / Heinrich, T. / Balint, J. / Rengachari, S. / Irlbacher, H. / Stockigt, D. / Bomer, U. / Bader, B. / Gradl, S.N. / Nising, C.F. / von Nussbaum, F. / Mumberg, D. / Panne, D. / Wengner, A.M.
History
DepositionMay 22, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation.year / _citation_author.name
Revision 1.2Feb 5, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)76,6842
Polymers76,1701
Non-polymers5141
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)153,3674
Polymers152,3402
Non-polymers1,0272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555y,x,-z1
Unit cell
Length a, b, c (Å)136.196, 136.196, 86.618
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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: 76170.055 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TBK1, NAK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UHD2, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-KHT / ~{N}-(cyclopropen-1-ylmethyl)-2-[[4-[[4-[3,3,3-tris(fluoranyl)propanoyl]piperazin-1-yl]methyl]pyridin-2-yl]amino]-1~{H}-benzimidazole-5-carboxamide


Mass: 513.515 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H26F3N7O2 / Feature type: SUBJECT OF INVESTIGATION

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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: 3.04 Å3/Da / Density % sol: 59.6 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / Details: 100 mM HEPES pH 7.5, 5-8% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Mar 19, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 3.15→48.75 Å / Num. obs: 13358 / % possible obs: 99.7 % / Redundancy: 8.1 % / Net I/σ(I): 13
Reflection shellResolution: 3.15→3.35 Å / Num. unique obs: 895

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Processing

Software
NameVersionClassification
PHENIX(1.15.2_3472: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.15→48.748 Å / SU ML: 0.67 / Cross valid method: FREE R-VALUE / σ(F): 1.26 / Phase error: 35.1
RfactorNum. reflection% reflection
Rfree0.3071 1574 5.06 %
Rwork0.2812 --
obs0.2824 31125 99.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.15→48.748 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5062 0 37 0 5099
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0025207
X-RAY DIFFRACTIONf_angle_d0.4237035
X-RAY DIFFRACTIONf_dihedral_angle_d6.8243132
X-RAY DIFFRACTIONf_chiral_restr0.037778
X-RAY DIFFRACTIONf_plane_restr0.003894
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1463-3.24780.43911700.44152602X-RAY DIFFRACTION98
3.2478-3.36390.41071360.39122703X-RAY DIFFRACTION100
3.3639-3.49850.36241570.36422700X-RAY DIFFRACTION100
3.4985-3.65770.40351420.38252664X-RAY DIFFRACTION100
3.6577-3.85050.37091340.33562694X-RAY DIFFRACTION100
3.8505-4.09160.34611540.31892669X-RAY DIFFRACTION100
4.0916-4.40730.34961470.29372724X-RAY DIFFRACTION100
4.4073-4.85050.2871360.28342672X-RAY DIFFRACTION100
4.8505-5.55150.29421350.28572711X-RAY DIFFRACTION100
5.5515-6.9910.35891390.29322696X-RAY DIFFRACTION100
6.991-48.7540.22041240.20962716X-RAY DIFFRACTION100

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