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- PDB-3elj: Jnk1 complexed with a bis-anilino-pyrrolopyrimidine inhibitor. -

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Basic information

Entry
Database: PDB / ID: 3elj
TitleJnk1 complexed with a bis-anilino-pyrrolopyrimidine inhibitor.
ComponentsMitogen-activated protein kinase 8
KeywordsTRANSFERASE / c-Jun N-terminal kinase / mitogen-activated protein kinase / ATP-binding / Kinase / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / JNK1
Function / homology
Function and homology information


positive regulation of cell killing / JUN phosphorylation / regulation of DNA replication origin binding / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity ...positive regulation of cell killing / JUN phosphorylation / regulation of DNA replication origin binding / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity / histone deacetylase regulator activity / positive regulation of NLRP3 inflammasome complex assembly / DSCAM interactions / protein serine/threonine kinase binding / NRAGE signals death through JNK / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / regulation of macroautophagy / mitogen-activated protein kinase / stress-activated MAPK cascade / response to mechanical stimulus / response to UV / JNK cascade / cellular response to cadmium ion / positive regulation of protein metabolic process / 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 / FCERI mediated MAPK activation / peptidyl-threonine phosphorylation / regulation of circadian rhythm / cellular response to reactive oxygen species / histone deacetylase binding / cellular response to mechanical stimulus / regulation of protein localization / cellular senescence / rhythmic process / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / cellular response to oxidative stress / peptidyl-serine phosphorylation / protein phosphatase binding / Oxidative Stress Induced Senescence / response to oxidative stress / cellular response to lipopolysaccharide / positive regulation of apoptotic process / axon / protein phosphorylation / 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. / Protein kinase domain ...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-GS7 / Mitogen-activated protein kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsChamberlain, S. / Atkins, C. / Deanda, F. / Dumble, M. / Gerding, R. / Groy, A. / Korenchuk, S. / Kumar, R. / Lei, H. / Mook, R. ...Chamberlain, S. / Atkins, C. / Deanda, F. / Dumble, M. / Gerding, R. / Groy, A. / Korenchuk, S. / Kumar, R. / Lei, H. / Mook, R. / Moorthy, G. / Redman, A. / Rowland, J. / Shewchuk, L. / Vicentini, G. / Mosley, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity.
Authors: Chamberlain, S.D. / Redman, A.M. / Wilson, J.W. / Deanda, F. / Shotwell, J.B. / Gerding, R. / Lei, H. / Yang, B. / Stevens, K.L. / Hassell, A.M. / Shewchuk, L.M. / Leesnitzer, M.A. / Smith, ...Authors: Chamberlain, S.D. / Redman, A.M. / Wilson, J.W. / Deanda, F. / Shotwell, J.B. / Gerding, R. / Lei, H. / Yang, B. / Stevens, K.L. / Hassell, A.M. / Shewchuk, L.M. / Leesnitzer, M.A. / Smith, J.L. / Sabbatini, P. / Atkins, C. / Groy, A. / Rowand, J.L. / Kumar, R. / Mook, R.A. / Moorthy, G. / Patnaik, S.
History
DepositionSep 22, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 30, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Sep 6, 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

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9932
Polymers42,5081
Non-polymers4851
Water5,855325
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.745, 71.465, 108.692
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 / Stress-activated protein kinase JNK1 / c-Jun N-terminal kinase 1 / JNK-46


Mass: 42508.191 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Expressed as a GST fusion protein. GST cleaved off with PreScission prior to crystallization.
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK8, JNK1, PRKM8 / Plasmid: pGEX 6P1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 DE3
References: UniProt: P45983, mitogen-activated protein kinase
#2: Chemical ChemComp-GS7 / 2-fluoro-6-{[2-({2-methoxy-4-[(methylsulfonyl)methyl]phenyl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide


Mass: 484.503 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21FN6O4S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 325 / 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: 2.32 Å3/Da / Density % sol: 46.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 18% peg3350, 0.1M sodium Hepes, 15% gylcerol added as a cryoprotectant prior to freezing., pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 22, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→59.76 Å / Num. all: 35293 / Num. obs: 35293 / % possible obs: 99.32 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Rmerge(I) obs: 0.096 / Net I/σ(I): 7.3
Reflection shellResolution: 1.8→1.847 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.191 / Num. unique all: 2545 / % possible all: 98.5

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2q01

2q01


Resolution: 1.8→59.76 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.939 / SU B: 4.65 / SU ML: 0.077 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R: 0.133 / ESU R Free: 0.121 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21538 1871 5 %RANDOM
Rwork0.18698 ---
obs0.18847 35293 99.32 %-
all-35293 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.945 Å2
Baniso -1Baniso -2Baniso -3
1-0.97 Å20 Å20 Å2
2---0.55 Å20 Å2
3----0.42 Å2
Refinement stepCycle: LAST / Resolution: 1.8→59.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2783 0 34 325 3142
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0223071
X-RAY DIFFRACTIONr_angle_refined_deg1.0411.9844196
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0535383
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.89824.307137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.19915537
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.1741517
X-RAY DIFFRACTIONr_chiral_restr0.0670.2452
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022461
X-RAY DIFFRACTIONr_nbd_refined0.1880.21446
X-RAY DIFFRACTIONr_nbtor_refined0.2990.22180
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1180.2279
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1050.252
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1090.222
X-RAY DIFFRACTIONr_mcbond_it0.5731.51927
X-RAY DIFFRACTIONr_mcangle_it0.80723039
X-RAY DIFFRACTIONr_scbond_it1.25131343
X-RAY DIFFRACTIONr_scangle_it1.9574.51157
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.248 133 -
Rwork0.215 2545 -
obs-2545 98.53 %
Refinement TLS params.

S12: 0.006 Å ° / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (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)
11.306-0.25730.41061.4382-0.45251.8652-0.0580.09980.164-0.0567-0.0691-0.02680.05090.1147-0.0296-0.01280.0019-0.05060.0092-0.064918.73213.99241.898
20.50070.08370.23120.58750.17051.3841-0.00760.05510.04590.0467-0.0425-0.05540.0097-0.0391-0.06030.0009-0.0066-0.059-0.0008-0.041315.36415.73815.675
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 112
2X-RAY DIFFRACTION2A113 - 365

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