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- PDB-4awi: Human Jnk1alpha kinase with 4-phenyl-7-azaindole IKK2 inhibitor. -

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Basic information

Entry
Database: PDB / ID: 4awi
TitleHuman Jnk1alpha kinase with 4-phenyl-7-azaindole IKK2 inhibitor.
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 8
KeywordsTRANSFERASE
Function / homology
Function and homology information


JUN phosphorylation / positive regulation of cell killing / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / positive regulation of establishment of protein localization to mitochondrion / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity ...JUN phosphorylation / positive regulation of cell killing / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / positive regulation of establishment of protein localization to mitochondrion / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity / histone deacetylase regulator activity / NRAGE signals death through JNK / positive regulation of NLRP3 inflammasome complex assembly / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / mitogen-activated protein kinase / regulation of macroautophagy / response to mechanical stimulus / response to UV / protein serine/threonine kinase binding / stress-activated MAPK cascade / energy homeostasis / JNK cascade / positive regulation of protein metabolic process / cellular response to cadmium ion / cellular response to amino acid starvation / NRIF signals cell death from the nucleus / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / negative regulation of protein binding / peptidyl-threonine phosphorylation / FCERI mediated MAPK activation / regulation of circadian rhythm / histone deacetylase binding / cellular response to mechanical stimulus / cellular response to reactive oxygen species / cellular senescence / rhythmic process / Signaling by ALK fusions and activated point mutants / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / regulation of protein localization / cellular response to oxidative stress / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / Oxidative Stress Induced Senescence / response to oxidative stress / positive regulation of apoptotic process / protein phosphorylation / axon / protein serine kinase activity / protein serine/threonine kinase activity / synapse / positive regulation of gene expression / negative regulation of apoptotic process / enzyme binding / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase, JNK / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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. ...Mitogen-activated protein (MAP) kinase, JNK / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / 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-AQ2 / Mitogen-activated protein kinase 8
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.91 Å
AuthorsChung, C. / Vicentini, G. / Liddle, J. / Bamborough, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: 4-Phenyl-7-Azaindoles as Potent, Selective and Bioavailable Ikk2 Inhibitors Demonstrating Good in Vivo Efficacy.
Authors: Liddle, J. / Bamborough, P. / Barker, M.D. / Campos, S. / Chung, C. / Cousins, R.P.C. / Faulder, P. / Heathcote, M.L. / Hobbs, H. / Holmes, D.S. / Ioannou, C. / Ramirez-Molina, C. / Morse, M. ...Authors: Liddle, J. / Bamborough, P. / Barker, M.D. / Campos, S. / Chung, C. / Cousins, R.P.C. / Faulder, P. / Heathcote, M.L. / Hobbs, H. / Holmes, D.S. / Ioannou, C. / Ramirez-Molina, C. / Morse, M.A. / Osborn, R. / Payne, J.J. / Pritchard, J.M. / Rumsey, W.L. / Tape, D.T. / Vicentini, G. / Whitworth, C. / Williamson, R.A.
History
DepositionJun 3, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2014Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1484
Polymers42,5081
Non-polymers6403
Water5,152286
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.438, 72.747, 110.155
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein MITOGEN-ACTIVATED PROTEIN KINASE 8 / MAP KINASE 8 / MAPK 8 / JNK-46 / STRESS-ACTIVATED PROTEIN KINASE 1C / SAPK1C / STRESS-ACTIVATED ...MAP KINASE 8 / MAPK 8 / JNK-46 / STRESS-ACTIVATED PROTEIN KINASE 1C / SAPK1C / STRESS-ACTIVATED PROTEIN KINASE JNK1 / C- JUN N-TERMINAL KINASE 1


Mass: 42508.191 Da / Num. of mol.: 1 / Fragment: RESIDUES 1-364
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: P45983, mitogen-activated protein kinase
#2: Chemical ChemComp-AQ2 / N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-[2-(1-methylethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]benzenesulfonamide


Mass: 447.571 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H25N3O4S2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 286 / 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: 2.38 Å3/Da / Density % sol: 48.26 % / Description: NONE
Crystal growpH: 6.5
Details: 0.05 M AMMONIUM SULFATE, 0.05 M BIS-TRIS PH 6.5, 30% V/V PENTAERYTHRITOL (15/4 EO/OH)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Type: ESRF / Wavelength: 0.931
DetectorType: ADSC CCD / Detector: CCD / Date: Jul 1, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 1.91→29.3 Å / Num. obs: 27663 / % possible obs: 89.3 % / Observed criterion σ(I): 2 / Redundancy: 2.8 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 10.2
Reflection shellResolution: 1.91→2 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 2.3 / % possible all: 86.4

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.91→28.5 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.935 / SU B: 6.817 / SU ML: 0.105 / Cross valid method: THROUGHOUT / ESU R: 0.186 / ESU R Free: 0.157 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.21941 1391 5 %RANDOM
Rwork0.18601 ---
obs0.18769 26266 86.49 %-
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: 29.267 Å2
Baniso -1Baniso -2Baniso -3
1-1.91 Å20 Å20 Å2
2---0.63 Å20 Å2
3----1.28 Å2
Refinement stepCycle: LAST / Resolution: 1.91→28.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2832 0 40 286 3158
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0193001
X-RAY DIFFRACTIONr_bond_other_d0.0060.022040
X-RAY DIFFRACTIONr_angle_refined_deg1.0121.974085
X-RAY DIFFRACTIONr_angle_other_deg0.83635005
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1395370
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.42624.632136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.57615540
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.461515
X-RAY DIFFRACTIONr_chiral_restr0.060.2448
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213297
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02585
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.914→1.964 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.284 92 -
Rwork0.269 1537 -
obs--72.79 %
Refinement TLS params.Method: refined / Origin x: 16.0622 Å / Origin y: 15.9303 Å / Origin z: 23.8644 Å
111213212223313233
T0.0104 Å2-0.0132 Å2-0.0083 Å2-0.0267 Å20.0051 Å2--0.0203 Å2
L0.0621 °2-0.0717 °20.0891 °2-0.1003 °2-0.0329 °2--0.4102 °2
S-0.0153 Å °0.0117 Å °0.0128 Å °0.0237 Å °-0.0158 Å °-0.0133 Å °-0.0021 Å °0.0009 Å °0.0311 Å °

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