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- PDB-5w5v: TBK1 co-crystal structure with amlexanox -

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Basic information

Entry
Database: PDB / ID: 5w5v
TitleTBK1 co-crystal structure with 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-ANW / Serine/threonine-protein kinase TBK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.645 Å
AuthorsBeyett, T.S. / Tesmer, J.J.G.
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
DepositionJun 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 27, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 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)76,3242
Polymers76,0261
Non-polymers2981
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)152,6484
Polymers152,0522
Non-polymers5972
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_675x-y+1,-y+2,-z+1/31
Buried area3690 Å2
ΔGint-5 kcal/mol
Surface area61950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)135.048, 135.048, 84.900
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) / Cell line: Spodoptera frugiperda cells / 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-ANW / 2-amino-7-(1-methylethyl)-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid


Mass: 298.293 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H14N2O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: antiinflammatory*YM

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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: 100 mM HEPES pH 7.5, 4% PEG 8000, 10% DMSO / PH range: 7.0-8.5

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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, 2016
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 3.645→39.903 Å / Num. obs: 18323 / % possible obs: 98.7 % / Observed criterion σ(I): -3 / Redundancy: 7.733 % / Biso Wilson estimate: 166.03 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.117 / Rrim(I) all: 0.125 / Χ2: 0.94 / Net I/av σ(I): 1.37 / Net I/σ(I): 14.67

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.79 Å48.16 Å
Translation6.79 Å48.16 Å

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASER2.7.16phasing
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4IM0

4im0


Resolution: 3.645→39.903 Å / SU ML: 0.57 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 32.54 / Details: Reference model restraints from PDB 4IM0
RfactorNum. reflection% reflection
Rfree0.2896 1806 9.86 %
Rwork0.229 --
obs0.2352 18323 94.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 367.59 Å2 / Biso mean: 185.0618 Å2 / Biso min: 98.05 Å2
Refinement stepCycle: final / Resolution: 3.645→39.903 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4865 0 22 0 4887
Biso mean--158.5 --
Num. residues----599
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034987
X-RAY DIFFRACTIONf_angle_d0.7736732
X-RAY DIFFRACTIONf_chiral_restr0.047750
X-RAY DIFFRACTIONf_plane_restr0.004851
X-RAY DIFFRACTIONf_dihedral_angle_d22.7471869
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.6454-3.74390.38851220.35681077119980
3.7439-3.8540.32571380.33581288142696
3.854-3.97830.35761340.31351287142196
3.9783-4.12030.3791460.29511262140896
4.1203-4.28510.42531310.2871288141996
4.2851-4.47990.26791410.25011301144296
4.4799-4.71570.31911510.24951300145196
4.7157-5.01060.31391390.22411271141096
5.0106-5.39660.2941340.23111294142896
5.3966-5.93810.33891390.28261300143997
5.9381-6.79370.33421330.27011299143297
6.7937-8.54560.33991560.21431298145498
8.5456-39.90530.19911420.16331252139493
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)
15.31431.06191.43123.1931.1395.23710.09820.40870.2243-0.5225-0.1190.8621-0.3201-0.4283-0.05191.12580.10410.01871.6618-0.06921.6569-37.2981134.7042-2.941
22.7268-2.0661.23723.4887-0.76231.58070.23880.55491.11690.0571-0.6524-0.5438-0.55950.65320.38741.2328-0.2573-0.08151.6857-0.00621.4006-12.6666141.211911.9344
34.6791.5753-2.59362.1424-0.51610.17760.3482-0.9258-1.24660.1493-0.4950.0007-0.13480.29560.08880.9117-0.0695-0.07192.02930.00920.77062.6443125.855925.5431
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 216 )A1 - 216
2X-RAY DIFFRACTION2chain 'A' and (resid 217 through 407 )A217 - 407
3X-RAY DIFFRACTION3chain 'A' and (resid 408 through 657 )A408 - 657

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