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- PDB-4l3p: Crystal Structure of 2-(1-benzothiophen-7-yl)-4-[1-(piperidin-4-y... -

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Basic information

Entry
Database: PDB / ID: 4l3p
TitleCrystal Structure of 2-(1-benzothiophen-7-yl)-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-amine 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 / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


histone kinase activity / positive regulation of cGAS/STING signaling pathway / 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 ...histone kinase activity / positive regulation of cGAS/STING signaling pathway / 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 / cellular response to angiotensin / positive regulation of vascular associated smooth muscle cell migration / anoikis / aorta development / MyD88-dependent toll-like receptor signaling pathway / interleukin-1-mediated signaling pathway / toll-like receptor 4 signaling pathway / cytoplasmic pattern recognition receptor signaling pathway / protein serine/threonine phosphatase activity / mitogen-activated protein kinase p38 binding / non-canonical NF-kappaB signal transduction / p38MAPK cascade / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon 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 / positive regulation of cell cycle / heart morphogenesis / protein serine/threonine kinase binding / stress-activated MAPK cascade / positive regulation of JUN kinase activity / JNK cascade / IRAK2 mediated activation of TAK1 complex / positive regulation of vascular associated smooth muscle cell proliferation / 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 / 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 / lung development / TAK1-dependent IKK and NF-kappa-B activation / 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 / cytoplasm / cytosol
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-1UH / 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: 2.68 Å
AuthorsWang, J. / Hornberger, K.R. / Crew, A.P. / Steinbacher, S. / Maskos, K. / Moertl, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1.
Authors: Hornberger, K.R. / Berger, D.M. / Crew, A.P. / Dong, H. / Kleinberg, A. / Li, A.H. / Medeiros, M.R. / Mulvihill, M.J. / Siu, K. / Tarrant, J. / Wang, J. / Weng, F. / Wilde, V.L. / ...Authors: Hornberger, K.R. / Berger, D.M. / Crew, A.P. / Dong, H. / Kleinberg, A. / Li, A.H. / Medeiros, M.R. / Mulvihill, M.J. / Siu, K. / Tarrant, J. / Wang, J. / Weng, F. / Wilde, V.L. / Albertella, M. / Bittner, M. / Cooke, A. / Gray, M.J. / Maresca, P. / May, E. / Meyn, P. / Peick, W. / Romashko, D. / Tanowitz, M. / Tokar, B.
History
DepositionJun 6, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 31, 2013Group: Database references
Revision 1.2Aug 7, 2013Group: Database references
Revision 1.3Jul 26, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.4Nov 15, 2017Group: Refinement description / Category: software
Revision 1.5Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

Downloads & links

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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)35,9362
Polymers35,5211
Non-polymers4161
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.299, 133.751, 144.502
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 / Tak1-Tab1 fusion protein / Transforming growth factor-beta-activated kinase 1 / TGF-beta-activated ...Tak1-Tab1 fusion protein / 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 / Fragment: SEE REMARK 999
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K7, TAK1, MAP3K7IP1, TAB1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O43318, UniProt: Q15750, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-1UH / 2-(1-benzothiophen-7-yl)-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-amine


Mass: 415.511 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21N5OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsPROTEIN IS A CHIMERA COMPRISING THE KINASE DOMAIN OF TAK1 (UNP O43318 RESIDUES 31-303) AND RESIDUES ...PROTEIN IS A CHIMERA COMPRISING THE KINASE DOMAIN OF TAK1 (UNP O43318 RESIDUES 31-303) AND RESIDUES 468-504 OF TAB1 (UNP Q15750).

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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: 68.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.75 M sodium citrate, 0.2 M sodium chloride, 0.1 M Tris, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.0001 / Wavelength: 1.0001 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 20, 2008 / Details: Dynamically bendable mirror
RadiationMonochromator: LN2 cooled fixed-exit Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0001 Å / Relative weight: 1
ReflectionResolution: 2.68→98.06 Å / Num. all: 16317 / Num. obs: 16317 / % possible obs: 92.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3 % / Rmerge(I) obs: 0.061
Reflection shellResolution: 2.68→2.89 Å / Redundancy: 3 % / Rmerge(I) obs: 0.437 / % possible all: 95.3

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2EVA

2eva


Resolution: 2.68→98.06 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.913 / SU B: 22.202 / SU ML: 0.244 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.454 / ESU R Free: 0.307 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26825 764 5.1 %RANDOM
Rwork0.2294 ---
all0.23137 14259 --
obs0.23137 14259 92.08 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 78.175 Å2
Baniso -1Baniso -2Baniso -3
1--5.3 Å20 Å20 Å2
2---2.75 Å20 Å2
3---8.05 Å2
Refinement stepCycle: LAST / Resolution: 2.68→98.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2342 0 30 1 2373
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222445
X-RAY DIFFRACTIONr_bond_other_d0.0010.022200
X-RAY DIFFRACTIONr_angle_refined_deg0.9921.9753322
X-RAY DIFFRACTIONr_angle_other_deg0.79135126
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3545293
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.58423.396106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.95615402
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1711515
X-RAY DIFFRACTIONr_chiral_restr0.0620.2345
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022692
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02503
X-RAY DIFFRACTIONr_nbd_refined0.1880.2583
X-RAY DIFFRACTIONr_nbd_other0.1640.22245
X-RAY DIFFRACTIONr_nbtor_refined0.1750.21191
X-RAY DIFFRACTIONr_nbtor_other0.080.21238
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1050.241
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0670.27
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1430.242
X-RAY DIFFRACTIONr_mcbond_it1.45821905
X-RAY DIFFRACTIONr_mcbond_other0.1882592
X-RAY DIFFRACTIONr_mcangle_it1.70532378
X-RAY DIFFRACTIONr_scbond_it1.9741191
X-RAY DIFFRACTIONr_scangle_it3.1026944
LS refinement shellResolution: 2.68→2.75 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.456 69 -
Rwork0.365 1054 -
obs--94.37 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.4621-0.58070.68614.4336-5.74537.44690.429-1.1945-0.71870.6628-0.2591-0.03080.6499-0.2652-0.16990.7037-0.18240.01170.7076-0.05370.4313-8.401-49.82-7.675
24.0782-0.273-0.55164.16050.28492.2361-0.0383-0.2191-0.3480.12420.0175-0.17920.20390.05440.0208-0.1964-0.0073-0.0197-0.21840.0584-0.1791-5.188-45.194-32.373
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A26 - 106
2X-RAY DIFFRACTION2A107 - 303

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