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- PDB-4o91: Crystal Structure of type II inhibitor NG25 bound to TAK1-TAB1 -

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Basic information

Entry
Database: PDB / ID: 4o91
TitleCrystal Structure of type II inhibitor NG25 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 chimera / Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway / TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 / 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-NG2 / 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: 2.393 Å
AuthorsGurbani, D. / Hunter, J.C. / Tan, L. / Westover, K.D.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of Type II Inhibitors of TGF beta-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2).
Authors: Tan, L. / Nomanbhoy, T. / Gurbani, D. / Patricelli, M. / Hunter, J. / Geng, J. / Herhaus, L. / Zhang, J. / Pauls, E. / Ham, Y. / Choi, H.G. / Xie, T. / Deng, X. / Buhrlage, S.J. / Sim, T. / ...Authors: Tan, L. / Nomanbhoy, T. / Gurbani, D. / Patricelli, M. / Hunter, J. / Geng, J. / Herhaus, L. / Zhang, J. / Pauls, E. / Ham, Y. / Choi, H.G. / Xie, T. / Deng, X. / Buhrlage, S.J. / Sim, T. / Cohen, P. / Sapkota, G. / Westover, K.D. / Gray, N.S.
History
DepositionDec 31, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 30, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2014Group: Database references
Revision 1.2Jan 28, 2015Group: Database references
Revision 1.3Aug 2, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.4Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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_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: 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)36,0012
Polymers35,4641
Non-polymers5381
Water2,000111
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera
hetero molecules

A: Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera
hetero molecules

A: Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera
hetero molecules

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)144,0068
Polymers141,8554
Non-polymers2,1504
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
crystal symmetry operation3_555-x,y,-z1
crystal symmetry operation4_545x,-y-1,-z1
Buried area4710 Å2
ΔGint-41 kcal/mol
Surface area52570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.214, 132.905, 145.498
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


Mass: 35463.867 Da / Num. of mol.: 1
Fragment: KINASE DOMAIN OF TAK1 (UNP O43318 RESIDUES 31-303) AND RESIDUES 468-504 OF TAB1 (UNP Q15750)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K7, MAP3K7 TAK1 TAB1 MAP3K7IP1, TAK1
Plasmid: Plasmid 30115: pFastBac His6 TEV LIC cloning vector (4B)
Cell line (production host): High Five / Production host: Trichoplusia ni (cabbage looper)
Strain (production host): High Five Cells (BTI-TN-5B1-4) clonal isolate derived from the parental Trichop ulsia ni cell line (cabbage looper ovary)
References: UniProt: O43318, UniProt: Q15750, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-NG2 / N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide


Mass: 537.576 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H30F3N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / 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: 3.97 Å3/Da / Density % sol: 69 %
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, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97926 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 7, 2013
RadiationMonochromator: Rosenbaum-Rock high-resolution double-crystal monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 2.35→98.13 Å / Num. obs: 22365 / % possible obs: 98.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.082

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASERphasing
PHENIXversion 1.8.4-1496refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.393→35.254 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.909 / SU ML: 0.26 / σ(F): 1.34 / Phase error: 27.54 / Stereochemistry target values: ML / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rfree0.2073 1121 5.01 %
Rwork0.1771 --
obs0.1786 22365 98.45 %
all-23480 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 68.84 Å2
Baniso -1Baniso -2Baniso -3
1--0.9 Å2-0 Å20 Å2
2---0.02 Å2-0 Å2
3---0.92 Å2
Refinement stepCycle: LAST / Resolution: 2.393→35.254 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2330 0 39 111 2480
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072441
X-RAY DIFFRACTIONf_angle_d0.9983317
X-RAY DIFFRACTIONf_dihedral_angle_d13.039919
X-RAY DIFFRACTIONf_chiral_restr0.036343
X-RAY DIFFRACTIONf_plane_restr0.005422
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3928-2.50170.32891340.27672499X-RAY DIFFRACTION95
2.5017-2.63350.28981400.23292592X-RAY DIFFRACTION97
2.6335-2.79840.26881380.20852608X-RAY DIFFRACTION98
2.7984-3.01440.24481390.19172664X-RAY DIFFRACTION100
3.0144-3.31760.24311410.19032660X-RAY DIFFRACTION100
3.3176-3.79710.21451390.172687X-RAY DIFFRACTION100
3.7971-4.78210.16231410.14852712X-RAY DIFFRACTION100
4.7821-35.25790.17431490.16722822X-RAY DIFFRACTION99

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