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- PDB-6cq5: TBK1 in Complex with Sulfone Analog of Amlexanox -

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Basic information

Entry
Database: PDB / ID: 6cq5
TitleTBK1 in Complex with Sulfone Analog of Amlexanox
ComponentsSerine/threonine-protein kinase TBK1
KeywordsTRANSFERASE / TBK1 / kinase / amlexanox
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 / TRAF6 mediated IRF7 activation / toll-like receptor 4 signaling pathway / cytoplasmic pattern recognition receptor signaling pathway / type I interferon-mediated signaling pathway / positive regulation of interferon-alpha production / positive regulation of macroautophagy / positive regulation of type I interferon production / canonical NF-kappaB signal transduction / positive regulation of autophagy / antiviral innate immune response / negative regulation of TORC1 signaling / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / activation of innate immune response / 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 / phosphoprotein binding / peptidyl-threonine phosphorylation / Regulation of TNFR1 signaling / 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 / 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-F8S / Serine/threonine-protein kinase TBK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.354 Å
AuthorsBeyett, T.S. / Tesmer, J.J.G.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK100319 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK060591 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK60597 United States
CitationJournal: Bioorg. Med. Chem. / Year: 2018
Title: Design, synthesis, and biological activity of substituted 2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid derivatives as inhibitors of the inflammatory kinases TBK1 and IKK epsilon ...Title: Design, synthesis, and biological activity of substituted 2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid derivatives as inhibitors of the inflammatory kinases TBK1 and IKK epsilon for the treatment of obesity.
Authors: Beyett, T.S. / Gan, X. / Reilly, S.M. / Gomez, A.V. / Chang, L. / Tesmer, J.J.G. / Saltiel, A.R. / Showalter, H.D.
History
DepositionMar 14, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 5, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)76,4142
Polymers76,0261
Non-polymers3881
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area31970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)134.840, 134.840, 85.157
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: 76025.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TBK1, NAK / Plasmid: pH7pFB / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: Q9UHD2, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-F8S / 2-amino-7-(1,1-dioxo-1lambda~6~-thian-4-yl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid / 7-[1,1-bis(oxidanylidene)thian-4-yl Analog of Amlexanox


Mass: 388.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16N2O6S / 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: 2.94 Å3/Da / Density % sol: 58.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1 M HEPES pH 7.5, 4% PEG 8000, 10% DMSO

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 15, 2017
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 3.35→48.155 Å / Num. obs: 12948 / % possible obs: 98.7 % / Redundancy: 7.717 % / Biso Wilson estimate: 115.87 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.101 / Rrim(I) all: 0.108 / Χ2: 0.93 / Net I/σ(I): 16.61
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
3.35-3.567.7071.1592.0420550.5781.24597.9
3.56-3.87.8820.5914.0219470.8820.63399.7
3.8-4.17.8890.2877.8418090.9690.30699.4
4.1-4.497.8360.14214.1516810.9940.15299.3
4.49-5.027.7950.08820.6415210.9970.09499.3
5.02-5.787.7760.08222.5513510.9970.08799.2
5.78-7.057.6920.06328.0911580.9980.06898.9
7.05-9.877.4770.0347.239060.9990.03298.1
9.87-48.1556.2640.02753.585220.9990.0393

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4IM0

4im0


Resolution: 3.354→48.155 Å / SU ML: 0.5 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 31.38
RfactorNum. reflection% reflection
Rfree0.2746 653 5.05 %
Rwork0.231 --
obs0.2332 12931 98.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 265.59 Å2 / Biso mean: 134.5705 Å2 / Biso min: 70.53 Å2
Refinement stepCycle: final / Resolution: 3.354→48.155 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4872 0 27 0 4899
Biso mean--102.58 --
Num. residues----602
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0025002
X-RAY DIFFRACTIONf_angle_d0.4126758
X-RAY DIFFRACTIONf_chiral_restr0.038749
X-RAY DIFFRACTIONf_plane_restr0.003858
X-RAY DIFFRACTIONf_dihedral_angle_d12.7533014
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.3538-3.4880.38141390.36272517265697
3.488-3.64670.32371420.337926202762100
3.6467-3.83890.3421400.290826002740100
3.8389-4.07930.28581420.261126372779100
4.0793-4.39410.2781360.238725732709100
4.3941-4.83590.28271340.2142638277299
4.8359-5.53480.26751400.23252581272199
5.5348-6.96990.30381360.25832597273399
6.9699-48.16030.21551290.16512536266596
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)
11.1159-0.489-0.08392.9421-0.41131.9098-0.08010.18290.3478-0.4212-0.0711-0.6926-0.06280.38980.18981.0076-0.24670.02830.97510.07391.05160.6955-35.2308-15.4856
22.59270.1036-0.88121.4378-0.32262.4062-0.58090.3167-0.4534-0.0940.0925-0.73840.75170.10030.50151.2309-0.1230.05340.73740.04451.2172-7.1171-60.3088-2.483
31.881.77280.58435.31091.70090.21390.0817-0.0429-0.0630.8074-0.20050.25160.25030.06960.09061.3122-0.272-0.02910.77270.08910.7188-27.322-65.130311.4132
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 0 through 228 )B - A0 - 228
2X-RAY DIFFRACTION2chain 'A' and (resid 229 through 407 )B - A229 - 407
3X-RAY DIFFRACTION3chain 'A' and (resid 408 through 657 )B - A408 - 657

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