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- PDB-4gs6: Irreversible Inhibition of TAK1 Kinase by 5Z-7-Oxozeaenol -

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Basic information

Entry
Database: PDB / ID: 4gs6
TitleIrreversible Inhibition of TAK1 Kinase by 5Z-7-Oxozeaenol
ComponentsTak1-Tab1 fusion protein
KeywordsTransferase/Transferase inhibitor / Kinase Fold / Tab1 binding / Cytosol / 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 / MAP kinase kinase kinase kinase activity / cardiac septum development / 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 / MAP kinase kinase kinase kinase activity / cardiac septum development / 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 / protein serine/threonine phosphatase activity / mitogen-activated protein kinase p38 binding / cytoplasmic pattern recognition receptor signaling pathway / 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 / JNK cascade / positive regulation of cell cycle / 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 / transforming growth factor beta receptor signaling pathway / TRAF6-mediated induction of TAK1 complex within TLR4 complex / 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 / positive regulation of non-canonical NF-kappaB signal transduction / NOD1/2 Signaling Pathway / 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 / molecular adaptor activity / cellular response to hypoxia / 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-1FM / 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 / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsLarsen, N.A. / Ferguson, A.D. / Wu, J.
CitationJournal: Acs Chem.Biol. / Year: 2013
Title: Mechanism and In Vitro Pharmacology of TAK1 Inhibition by (5Z)-7-Oxozeaenol.
Authors: Wu, J. / Powell, F. / Larsen, N.A. / Lai, Z. / Byth, K.F. / Read, J. / Gu, R.F. / Roth, M. / Toader, D. / Saeh, J.C. / Chen, H.
History
DepositionAug 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2013Group: Database references
Revision 1.2Aug 2, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tak1-Tab1 fusion protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,50412
Polymers35,5211
Non-polymers98311
Water2,864159
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.138, 133.867, 142.129
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 Tak1-Tab1 fusion protein / 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: 35520.918 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-1FM / (3S,5Z,8S,9S,11E)-8,9,16-trihydroxy-14-methoxy-3-methyl-3,4,9,10-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione / (5Z)-7-Oxozeaenol


Mass: 362.374 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22O7
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 159 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.89 Å3/Da / Density % sol: 68.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.55-0.75 M sodium citrate, 0.2 M NaCl, 0.1 M Tris, and 5mM adenosine. Adenosine bound crystals are backsoaked with inhibitor, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ DW / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Oct 3, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.2→18.75 Å / Num. all: 28636 / Num. obs: 28551 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 6 % / Biso Wilson estimate: 52.85 Å2 / Rmerge(I) obs: 0.094 / Net I/σ(I): 7.8
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.484 / Mean I/σ(I) obs: 2 / Num. unique all: 2968 / % possible all: 100

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
BUSTER2.11.2refinement
d*TREKdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→18.75 Å / Cor.coef. Fo:Fc: 0.9426 / Cor.coef. Fo:Fc free: 0.9304 / SU R Cruickshank DPI: 0.183 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2451 1442 5.05 %RANDOM
Rwork0.2221 ---
obs0.2232 28551 99.85 %-
all-28551 --
Displacement parametersBiso mean: 67.48 Å2
Baniso -1Baniso -2Baniso -3
1-8.5816 Å20 Å20 Å2
2--0.7573 Å20 Å2
3----9.3388 Å2
Refine analyzeLuzzati coordinate error obs: 0.397 Å
Refinement stepCycle: LAST / Resolution: 2.2→18.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2334 0 66 159 2559
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012480HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.13347HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d17.97832SINUSOIDAL2
LS refinement shellResolution: 2.2→2.28 Å / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.2709 162 5.46 %
Rwork0.2522 2806 -
all0.2532 2968 -
obs-2968 99.85 %
Refinement TLS params.Method: refined / Origin x: 22.0209 Å / Origin y: 21.166 Å / Origin z: 44.7101 Å
111213212223313233
T-0.2736 Å2-0.0077 Å2-0.0081 Å2--0.247 Å20.087 Å2---0.1767 Å2
L2.9461 °20.2246 °2-0.196 °2-2.4184 °2-0.4525 °2--1.3387 °2
S0.0191 Å °-0.3975 Å °-0.3159 Å °0.2763 Å °-0.028 Å °-0.0367 Å °0.1072 Å °-0.0465 Å °0.009 Å °

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