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- PDB-5j8i: Crystal structure of TL11-113 bound to TAK1-TAB1 -

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Basic information

Entry
Database: PDB / ID: 5j8i
TitleCrystal structure of TL11-113 bound to TAK1-TAB1
ComponentsMitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera
KeywordsTRANSFERASE/TRANSFERASE inhibitor / Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


positive regulation of cGAS/STING signaling pathway / histone kinase activity / MAP kinase kinase kinase kinase activity / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / linear polyubiquitin binding / interleukin-17A-mediated signaling pathway / cardiac septum development / I-kappaB phosphorylation / mitogen-activated protein kinase kinase kinase / interleukin-33-mediated signaling pathway ...positive regulation of cGAS/STING signaling pathway / histone kinase activity / MAP kinase kinase kinase kinase activity / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / linear polyubiquitin binding / interleukin-17A-mediated signaling pathway / 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 / activation of NF-kappaB-inducing kinase activity / coronary vasculature development / ATAC complex / positive regulation of vascular associated smooth muscle cell migration / cellular response to angiotensin / anoikis / aorta development / MyD88-dependent toll-like receptor signaling pathway / interleukin-1-mediated signaling pathway / toll-like receptor 4 signaling pathway / protein serine/threonine kinase binding / protein serine/threonine phosphatase activity / mitogen-activated protein kinase p38 binding / cytoplasmic pattern recognition receptor signaling pathway / p38MAPK cascade / non-canonical NF-kappaB signal transduction / Fc-epsilon receptor signaling pathway / stimulatory C-type lectin receptor signaling pathway / positive regulation of macroautophagy / positive regulation of cell size / MAP kinase kinase kinase activity / MAP kinase activity / canonical NF-kappaB signal transduction / enzyme activator activity / positive regulation of cell cycle / stress-activated MAPK cascade / heart morphogenesis / positive regulation of JUN kinase activity / JNK cascade / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / 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 / protein serine/threonine kinase activator activity / transforming growth factor beta receptor signaling pathway / 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 / Activation of NF-kappaB in B cells / TAK1-dependent IKK and NF-kappa-B activation / lung development / NOD1/2 Signaling Pathway / positive regulation of protein serine/threonine kinase activity / receptor tyrosine kinase binding / positive regulation of T cell cytokine production / CLEC7A (Dectin-1) signaling / transcription coactivator binding / FCERI mediated NF-kB activation / Interleukin-1 signaling / positive regulation of non-canonical NF-kappaB signal transduction / MAPK cascade / Downstream TCR signaling / Ca2+ pathway / cellular response to tumor necrosis factor / T cell receptor signaling pathway / cellular response to hypoxia / scaffold protein binding / DNA-binding transcription factor binding / positive regulation of canonical NF-kappaB signal transduction / in utero embryonic development / positive regulation of MAPK cascade / molecular adaptor activity / endosome membrane / Ub-specific processing proteases / nuclear speck / defense response to bacterium / inflammatory response / immune response / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / protein-containing complex binding / endoplasmic reticulum membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / magnesium ion binding / endoplasmic reticulum / protein-containing complex / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase kinase kinase 7 / : / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain ...Mitogen-activated protein (MAP) kinase kinase kinase 7 / : / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-6H4 / 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: 2.404 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 7, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 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

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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)35,9292
Polymers35,4641
Non-polymers4651
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.248, 133.343, 145.039
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: 35463.867 Da / Num. of mol.: 1
Fragment: UNP O43318 residues 31-303, Q15750 residues 468-504
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-6H4 / N-{2-[(5-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}prop-2-enamide


Mass: 464.947 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H25ClN6O2

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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: 3.97 Å3/Da / Density % sol: 69.02 %
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, 5mM Adenosine;

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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: Oct 15, 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: 2.43→50 Å / Num. obs: 21238 / % possible obs: 96.3 % / Redundancy: 8.3 % / Rmerge(I) obs: 0.124 / Net I/σ(I): 18.94
Reflection shellResolution: 2.43→2.47 Å / Redundancy: 5.6 % / Rmerge(I) obs: 1.571 / Mean I/σ(I) obs: 1.16 / % possible all: 80.1

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
DENZOdata reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YIY

2yiy


Resolution: 2.404→49.081 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 33.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2444 1057 4.99 %
Rwork0.2226 --
obs0.2237 21171 94.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.404→49.081 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2301 0 33 0 2334
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032403
X-RAY DIFFRACTIONf_angle_d0.6063258
X-RAY DIFFRACTIONf_dihedral_angle_d10.8931431
X-RAY DIFFRACTIONf_chiral_restr0.041340
X-RAY DIFFRACTIONf_plane_restr0.005414
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.404-2.51340.3926980.34951826X-RAY DIFFRACTION69
2.5134-2.64590.38851140.31072322X-RAY DIFFRACTION88
2.6459-2.81160.32351400.29442525X-RAY DIFFRACTION97
2.8116-3.02870.31561440.25812641X-RAY DIFFRACTION100
3.0287-3.33340.30621400.24072634X-RAY DIFFRACTION100
3.3334-3.81560.23121390.21412669X-RAY DIFFRACTION100
3.8156-4.80660.20861340.19722684X-RAY DIFFRACTION100
4.8066-49.09150.20781480.20062813X-RAY DIFFRACTION100

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