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- PDB-6boe: TBK1 in complex with amide-coupled tetrazole analog of amlexanox -

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Basic information

Entry
Database: PDB / ID: 6boe
TitleTBK1 in complex with amide-coupled tetrazole analog of amlexanox
ComponentsSerine/threonine-protein kinase TBK1
KeywordsTRANSFERASE / TBK1 / kinase / amlexanox / obesity / diabetes
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 / 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 / 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-E0S / Serine/threonine-protein kinase TBK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.598 Å
AuthorsBeyett, T.S. / Tesmer, J.J.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01 DK100319 United States
CitationJournal: Mol. Pharmacol. / Year: 2018
Title: Carboxylic Acid Derivatives of Amlexanox Display Enhanced Potency toward TBK1 and IKKepsilonand Reveal Mechanisms for Selective Inhibition.
Authors: Beyett, T.S. / Gan, X. / Reilly, S.M. / Chang, L. / Gomez, A.V. / Saltiel, A.R. / Showalter, H.D. / Tesmer, J.J.G.
History
DepositionNov 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 26, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)76,3912
Polymers76,0261
Non-polymers3651
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area31970 Å2
Unit cell
Length a, b, c (Å)134.483, 134.483, 85.499
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 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UHD2, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-E0S / 2-amino-5-oxo-7-(propan-2-yl)-N-(1H-tetrazol-5-yl)-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxamide


Mass: 365.346 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N7O3

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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: 2.93 Å3/Da / Density % sol: 57.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1 M HEPES pH 7.5, 5% PEG 8000 / PH range: 7.0-8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.03312 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 12, 2017
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03312 Å / Relative weight: 1
ReflectionResolution: 3.6→35.349 Å / Num. obs: 10637 / % possible obs: 99.9 % / Redundancy: 18.985 % / Biso Wilson estimate: 166.12 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.141 / Rrim(I) all: 0.145 / Χ2: 0.967 / Net I/σ(I): 16.36 / Num. measured all: 201948
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
3.6-3.8220.0011.5791.5534062171117030.6681.6299.5
3.82-4.0819.1210.9163.0630460159415930.8870.94199.9
4.08-4.418.7860.4696.5227390145914580.9740.48399.9
4.4-4.8220.0560.27212.0527858138913890.9930.279100
4.82-5.3819.6360.20616.3724290123712370.9950.211100
5.38-6.2119.0590.18617.2920965110011000.9950.191100
6.21-7.5817.4840.10628.7166279519510.9990.11100
7.58-10.6316.9850.06157.181277375275210.063100
10.63-35.34916.570.05567.59752345945410.05798.9

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.84 Å48.13 Å
Translation6.84 Å48.13 Å

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
XSCALE0.5.32data scaling
PHASER2.7.16phasing
PDB_EXTRACT3.22data extraction
Cootmodel building
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4IM0

4im0


Resolution: 3.598→35.349 Å / SU ML: 0.59 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 34.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2911 1064 9.85 %
Rwork0.2414 18025 -
obs0.2465 10591 99.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 293.14 Å2 / Biso mean: 182.1693 Å2 / Biso min: 113.93 Å2
Refinement stepCycle: final / Resolution: 3.598→35.349 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4868 0 27 0 4895
Biso mean--187.27 --
Num. residues----600
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0014997
X-RAY DIFFRACTIONf_angle_d0.3956745
X-RAY DIFFRACTIONf_chiral_restr0.037747
X-RAY DIFFRACTIONf_plane_restr0.003855
X-RAY DIFFRACTIONf_dihedral_angle_d6.2483008
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.5982-3.68810.45251400.42771286142698
3.6881-3.78770.38031420.364812831425100
3.7877-3.8990.38421510.320312861437100
3.899-4.02470.35961370.317112971434100
4.0247-4.16830.34611290.298512791408100
4.1683-4.33490.31791420.247413191461100
4.3349-4.53180.28591440.244812871431100
4.5318-4.77020.29561400.239912901430100
4.7702-5.06830.26961400.231312821422100
5.0683-5.45830.29661440.259212871431100
5.4583-6.00520.40011420.294212951437100
6.0052-6.86860.35141360.293413051441100
6.8686-8.63280.29161320.232612881420100
8.6328-35.35030.19991500.16041241139196
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)
19.1575-7.2281-5.58578.8775.24456.0375-0.43230.81921.44770.80670.9133-1.2941.6419-0.2351-0.54772.1334-0.1407-0.18091.76880.33831.6915-0.2388-21.8694-21.2621
24.5729-1.5725-1.95529.5417-4.52769.6639-0.13940.74720.7105-0.794-0.5544-0.5739-0.20780.57010.70931.2226-0.3581-0.07431.60840.07141.1633-2.8901-36.5681-16.974
30.30770.37840.44486.05820.43858.8112-0.13680.9870.4513-0.2-0.3028-0.95290.17610.67060.67561.9264-0.2607-0.21011.59730.27811.4332-1.9529-39.4561-15.8047
42.32930.02291.29247.4714-2.2989.4732-0.7038-0.00890.5522-0.0633-0.0957-1.8786-0.45652.51470.69841.7503-0.0031-0.15192.08860.30642.085412.2067-48.4426-3.9668
55.78821.4631-1.24171.530.45941.584-0.61630.964-1.2395-0.37540.4235-0.66330.8759-0.27220.26782.0954-0.16540.14581.3875-0.07241.3719-8.8434-62.884-6.1463
62.532.715-2.41958.558-0.66942.4832-0.650.3521-0.4515-0.86240.2925-1.57740.81720.00930.30981.6528-0.0059-0.13661.29970.06091.2066-11.6544-54.0998.1502
73.9654.15071.37167.92613.56061.13220.7542-0.375-0.27841.8084-1.01550.78680.6875-0.15090.2112.0183-0.2996-0.2741.26830.14351.62-36.1223-77.56299.493
84.90124.73810.01097.21651.45382.30450.3824-0.2240.10060.9484-0.1076-0.1501-0.1686-0.2738-0.20911.7578-0.0664-0.3161.42560.07881.3177-13.0995-37.955115.1083
95.63073.23993.29723.39393.7577-0.26160.1416-0.3983-0.84130.8696-0.2869-0.01130.4653-0.26740.2482.7181-0.61010.18441.77940.11611.1963-33.6654-83.77079.1557
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 0 through 60 )A0 - 60
2X-RAY DIFFRACTION2chain 'A' and (resid 61 through 129 )A61 - 129
3X-RAY DIFFRACTION3chain 'A' and (resid 130 through 176 )A130 - 176
4X-RAY DIFFRACTION4chain 'A' and (resid 177 through 246 )A177 - 246
5X-RAY DIFFRACTION5chain 'A' and (resid 247 through 369 )A247 - 369
6X-RAY DIFFRACTION6chain 'A' and (resid 370 through 409 )A370 - 409
7X-RAY DIFFRACTION7chain 'A' and (resid 410 through 525 )A410 - 525
8X-RAY DIFFRACTION8chain 'A' and (resid 526 through 604 )A526 - 604
9X-RAY DIFFRACTION9chain 'A' and (resid 605 through 657 )A605 - 657

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