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- PDB-5v5n: Crystal structure of Takinib bound to TAK1 -

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Basic information

Entry
Database: PDB / ID: 5v5n
TitleCrystal structure of Takinib bound to TAK1
ComponentsMitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera
KeywordsTRANSFERASE/TRANSFERASE inhibitor / TAK1 / inhibitor / hydrogen bond / DFG-in / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


histone kinase activity / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / linear polyubiquitin binding / interleukin-17A-mediated signaling pathway / cardiac septum development / MAP kinase kinase kinase kinase activity / I-kappaB phosphorylation / mitogen-activated protein kinase kinase kinase / interleukin-33-mediated signaling pathway / toll-like receptor 3 signaling pathway ...histone kinase activity / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / linear polyubiquitin binding / interleukin-17A-mediated signaling pathway / cardiac septum development / MAP kinase kinase kinase kinase activity / I-kappaB phosphorylation / mitogen-activated protein kinase kinase kinase / interleukin-33-mediated signaling pathway / toll-like receptor 3 signaling pathway / type II transforming growth factor beta receptor binding / TRIF-dependent toll-like receptor signaling pathway / positive regulation of cGAS/STING signaling pathway / JUN kinase kinase kinase activity / coronary vasculature development / ATAC complex / positive regulation of vascular associated smooth muscle cell migration / anoikis / non-canonical NF-kappaB signal transduction / interleukin-1-mediated signaling pathway / aorta development / MyD88-dependent toll-like receptor signaling pathway / toll-like receptor 4 signaling pathway / mitogen-activated protein kinase p38 binding / cytoplasmic pattern recognition receptor signaling pathway / protein serine/threonine phosphatase activity / p38MAPK cascade / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / positive regulation of macroautophagy / positive regulation of JUN kinase activity / cellular response to angiotensin / MAP kinase activity / MAP kinase kinase kinase activity / canonical NF-kappaB signal transduction / positive regulation of cell size / heart morphogenesis / stress-activated MAPK cascade / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of cell cycle / JNK cascade / protein serine/threonine kinase binding / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / TICAM1,TRAF6-dependent induction of TAK1 complex / positive regulation of interleukin-2 production / TRAF6-mediated induction of TAK1 complex within TLR4 complex / transforming growth factor beta receptor signaling pathway / protein serine/threonine kinase activator activity / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / TNFR1-induced NF-kappa-B signaling pathway / activated TAK1 mediates p38 MAPK activation / lung development / Activation of NF-kappaB in B cells / transcription coactivator binding / TAK1-dependent IKK and NF-kappa-B activation / NOD1/2 Signaling Pathway / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of T cell cytokine production / receptor tyrosine kinase binding / CLEC7A (Dectin-1) signaling / FCERI mediated NF-kB activation / Interleukin-1 signaling / MAPK cascade / Downstream TCR signaling / cellular response to tumor necrosis factor / T cell receptor signaling pathway / Ca2+ pathway / scaffold protein binding / DNA-binding transcription factor binding / cellular response to hypoxia / molecular adaptor activity / in utero embryonic development / positive regulation of canonical NF-kappaB signal transduction / positive regulation of MAPK cascade / endosome membrane / Ub-specific processing proteases / defense response to bacterium / immune response / inflammatory response / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / endoplasmic reticulum membrane / protein-containing complex binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / magnesium ion binding / endoplasmic reticulum / signal transduction / protein-containing complex / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Protein phosphatase 2C / Protein phosphatase 2C family / Serine/threonine phosphatases, family 2C, catalytic domain / PPM-type phosphatase domain profile. / PPM-type phosphatase-like domain / PPM-type phosphatase-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 ...: / Protein phosphatase 2C / Protein phosphatase 2C family / Serine/threonine phosphatases, family 2C, catalytic domain / PPM-type phosphatase domain profile. / PPM-type phosphatase-like domain / PPM-type phosphatase-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-EDH / Mitogen-activated protein kinase kinase kinase 7 / TGF-beta-activated kinase 1 and MAP3K7-binding protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.006 Å
AuthorsGurbani, D. / Westover, K. / Bera, A.K.
CitationJournal: Cell Chem Biol / Year: 2017
Title: Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-alpha Inhibition for Cancer and Autoimmune Disease.
Authors: Totzke, J. / Gurbani, D. / Raphemot, R. / Hughes, P.F. / Bodoor, K. / Carlson, D.A. / Loiselle, D.R. / Bera, A.K. / Eibschutz, L.S. / Perkins, M.M. / Eubanks, A.L. / Campbell, P.L. / Fox, D. ...Authors: Totzke, J. / Gurbani, D. / Raphemot, R. / Hughes, P.F. / Bodoor, K. / Carlson, D.A. / Loiselle, D.R. / Bera, A.K. / Eibschutz, L.S. / Perkins, M.M. / Eubanks, A.L. / Campbell, P.L. / Fox, D.A. / Westover, K.D. / Haystead, T.A.J. / Derbyshire, E.R.
History
DepositionMar 14, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 30, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 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: Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1032
Polymers34,7811
Non-polymers3221
Water2,072115
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.340, 134.227, 143.385
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera / Transforming growth factor-beta-activated kinase 1 / TGF-beta-activated kinase 1 / Mitogen- ...Transforming growth factor-beta-activated kinase 1 / TGF-beta-activated kinase 1 / Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 / TGF-beta-activated kinase 1-binding protein 1 / TAK1-binding protein 1


Mass: 34781.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K7, TAK1, TAB1, MAP3K7IP1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O43318, UniProt: Q15750, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-EDH / N~1~-(1-propyl-1,3-dihydro-2H-benzimidazol-2-ylidene)benzene-1,3-dicarboxamide / EDHS-206


Mass: 322.361 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 115 / 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: 4.04 Å3/Da / Density % sol: 69.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.75M NaCitrate, 0.1M Tris-HCL, 0.2M NaCl, pH 7.0, 10mM DTT. 20% Ethyleneglycol as cryoprotectant.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97914 Å
DetectorType: DECTRIS PILATUS3 X 6M / Detector: PIXEL / Date: Feb 16, 2017
RadiationMonochromator: YES / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97914 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 34990 / % possible obs: 91.8 % / Redundancy: 11.6 % / Biso Wilson estimate: 36.68 Å2 / Rmerge(I) obs: 0.065 / Net I/σ(I): 28.46
Reflection shellResolution: 2→2.03 Å / Rmerge(I) obs: 0.763 / Mean I/σ(I) obs: 1.59 / CC1/2: 0.904

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Processing

Software
NameVersionClassification
PHENIX(dev_2341: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2EVA

2eva


Resolution: 2.006→48.995 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 27.77 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.222 1734 4.97 %
Rwork0.1925 --
obs0.194 34916 91.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.006→48.995 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2337 0 24 115 2476
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032447
X-RAY DIFFRACTIONf_angle_d0.5333328
X-RAY DIFFRACTIONf_dihedral_angle_d14.4331459
X-RAY DIFFRACTIONf_chiral_restr0.041349
X-RAY DIFFRACTIONf_plane_restr0.004427
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0056-2.06460.3866860.29241853X-RAY DIFFRACTION62
2.0646-2.13130.29571150.26232117X-RAY DIFFRACTION71
2.1313-2.20740.26971190.24672393X-RAY DIFFRACTION80
2.2074-2.29580.27271290.24162663X-RAY DIFFRACTION89
2.2958-2.40030.2511600.22362878X-RAY DIFFRACTION96
2.4003-2.52680.22881520.20542968X-RAY DIFFRACTION99
2.5268-2.68520.22441600.2053010X-RAY DIFFRACTION100
2.6852-2.89250.24741590.21452979X-RAY DIFFRACTION100
2.8925-3.18350.22681590.21343034X-RAY DIFFRACTION100
3.1835-3.6440.23551680.19993049X-RAY DIFFRACTION100
3.644-4.59050.19761610.15823047X-RAY DIFFRACTION100
4.5905-49.00990.19281660.17113191X-RAY DIFFRACTION99

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