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- PDB-5jk3: Crystal structure of TL11-128 bound to TAK1-TAB1 -

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Basic information

Entry
Database: PDB / ID: 5jk3
TitleCrystal structure of TL11-128 bound to TAK1-TAB1
ComponentsMitogen-activated protein kinase kinase kinase 7,TGF-beta-activated kinase 1 and MAP3K7-binding protein 1
KeywordsTransferase/Transferase Inhibitor / Mitogen activated protein kinase kinase kinase 7 / TGF-beta activated Kinase 1 and MAP3K7-binding protein 1 chimera / Serine/threonine kinase which act as essential component of the MAP kinase signal transduction pathway / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


I-kappaB phosphorylation / histone kinase activity / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / linear polyubiquitin binding / cardiac septum development / interleukin-17A-mediated signaling pathway / MAP kinase kinase kinase kinase activity / mitogen-activated protein kinase kinase kinase / interleukin-33-mediated signaling pathway / toll-like receptor 3 signaling pathway ...I-kappaB phosphorylation / histone kinase activity / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / linear polyubiquitin binding / cardiac septum development / interleukin-17A-mediated signaling pathway / MAP kinase kinase kinase kinase activity / 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 / coronary vasculature development / ATAC complex / positive regulation of vascular associated smooth muscle cell migration / non-canonical NF-kappaB signal transduction / anoikis / interleukin-1-mediated signaling pathway / MyD88-dependent toll-like receptor signaling pathway / aorta development / toll-like receptor 4 signaling pathway / mitogen-activated protein kinase p38 binding / cytoplasmic pattern recognition receptor signaling pathway / p38MAPK cascade / Fc-epsilon receptor signaling pathway / stimulatory C-type lectin receptor signaling pathway / positive regulation of JUN kinase activity / protein serine/threonine phosphatase activity / cellular response to angiotensin / positive regulation of macroautophagy / MAP kinase activity / positive regulation of cell size / canonical NF-kappaB signal transduction / MAP kinase kinase kinase activity / heart morphogenesis / stress-activated MAPK cascade / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of cell cycle / JNK cascade / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / positive regulation of interleukin-2 production / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / TICAM1,TRAF6-dependent induction of TAK1 complex / TRAF6-mediated induction of TAK1 complex within TLR4 complex / transforming growth factor beta receptor signaling pathway / protein serine/threonine kinase binding / lung development / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / protein serine/threonine kinase activator activity / TNFR1-induced NF-kappa-B signaling pathway / activated TAK1 mediates p38 MAPK activation / Activation of NF-kappaB in B cells / positive regulation of non-canonical NF-kappaB signal transduction / NOD1/2 Signaling Pathway / TAK1-dependent IKK and NF-kappa-B activation / positive regulation of T cell cytokine production / receptor tyrosine kinase binding / CLEC7A (Dectin-1) signaling / FCERI mediated NF-kB activation / transcription coactivator binding / Interleukin-1 signaling / cellular response to tumor necrosis factor / Downstream TCR signaling / T cell receptor signaling pathway / MAPK cascade / Ca2+ pathway / scaffold protein binding / cellular response to hypoxia / molecular adaptor activity / DNA-binding transcription factor binding / 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 / cytoplasm / cytosol
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-6L4 / 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: 2.371 Å
AuthorsGurbani, D. / Westover, K.D.
Funding support United States, 1items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)CPRIT R1207 and CPRIT RP140233 United States
CitationJournal: Bioorg. Med. Chem. / Year: 2017
Title: Structure-guided development of covalent TAK1 inhibitors.
Authors: Tan, L. / Gurbani, D. / Weisberg, E.L. / Hunter, J.C. / Li, L. / Jones, D.S. / Ficarro, S.B. / Mowafy, S. / Tam, C.P. / Rao, S. / Du, G. / Griffin, J.D. / Sorger, P.K. / Marto, J.A. / Westover, K.D. / Gray, N.S.
History
DepositionApr 25, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 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
Revision 1.4Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8352
Polymers35,4641
Non-polymers3711
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.272, 133.585, 144.202
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 / 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: 35463.867 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-6L4 / ~{N}-[2-[5-chloranyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide / N-(2-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide


Mass: 370.793 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15ClN6O2
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: 3.96 Å3/Da / Density % sol: 68.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.65-0.75 M sodium citrate, 0.2 M NaCl, 0.1 M Tris, and 5mM adenosine. Adenosine bound TAK1-TAB1 crystals are backsoaked with inhibitor, pH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97932 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 19, 2015
RadiationMonochromator: Rosenbaum-Rock high-resolution double-crystal monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97932 Å / Relative weight: 1
ReflectionResolution: 2.37→50 Å / Num. obs: 21503 / % possible obs: 93.7 % / Redundancy: 5.9 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 17.19
Reflection shellResolution: 2.37→2.44 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.805 / Mean I/σ(I) obs: 2.05 / CC1/2: 0.76 / % possible all: 69.7

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YIY

2yiy


Resolution: 2.371→35.381 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 34.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2658 1071 4.99 %
Rwork0.2348 --
obs0.2363 21465 92.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.371→35.381 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2146 0 26 0 2172
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032233
X-RAY DIFFRACTIONf_angle_d0.5693025
X-RAY DIFFRACTIONf_dihedral_angle_d10.3111328
X-RAY DIFFRACTIONf_chiral_restr0.041320
X-RAY DIFFRACTIONf_plane_restr0.004384
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.371-2.47880.3247880.29061643X-RAY DIFFRACTION61
2.4788-2.60950.3621100.2952237X-RAY DIFFRACTION82
2.6095-2.77290.33581420.27492609X-RAY DIFFRACTION95
2.7729-2.98690.28541440.27282710X-RAY DIFFRACTION100
2.9869-3.28730.31221430.25992756X-RAY DIFFRACTION100
3.2873-3.76250.28561450.23612742X-RAY DIFFRACTION100
3.7625-4.73860.24351450.21012785X-RAY DIFFRACTION100
4.7386-35.38490.22771540.21742912X-RAY DIFFRACTION100

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