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- PDB-4hyu: Crystal structure of JNK1 in complex with JIP1 peptide and 4-{4-[... -

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Basic information

Entry
Database: PDB / ID: 4hyu
TitleCrystal structure of JNK1 in complex with JIP1 peptide and 4-{4-[4-(3-Methanesulfonyl-propoxy)-indazol-1-yl]-pyrimidin-2-ylamino}-cyclohexan
Components
  • C-Jun-amino-terminal kinase-interacting protein 1
  • Mitogen-activated protein kinase 8
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


dentate gyrus mossy fiber / regulation of CD8-positive, alpha-beta T cell proliferation / JUN phosphorylation / positive regulation of cell killing / basal dendrite / Activation of BMF and translocation to mitochondria / Interleukin-38 signaling / negative regulation of JUN kinase activity / positive regulation of establishment of protein localization to mitochondrion / JUN kinase activity ...dentate gyrus mossy fiber / regulation of CD8-positive, alpha-beta T cell proliferation / JUN phosphorylation / positive regulation of cell killing / basal dendrite / Activation of BMF and translocation to mitochondria / Interleukin-38 signaling / negative regulation of JUN kinase activity / positive regulation of establishment of protein localization to mitochondrion / JUN kinase activity / Activation of BIM and translocation to mitochondria / WNT5:FZD7-mediated leishmania damping / MAP-kinase scaffold activity / JUN kinase binding / positive regulation of cyclase activity / regulation of JNK cascade / mitogen-activated protein kinase kinase binding / mitogen-activated protein kinase kinase kinase binding / histone deacetylase regulator activity / NRAGE signals death through JNK / cellular response to stress / Activation of the AP-1 family of transcription factors / positive regulation of NLRP3 inflammasome complex assembly / Fc-epsilon receptor signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / protein kinase inhibitor activity / dendritic growth cone / positive regulation of protein metabolic process / peptidyl-threonine phosphorylation / MAP kinase activity / kinesin binding / mitogen-activated protein kinase / regulation of macroautophagy / response to mechanical stimulus / axonal growth cone / stress-activated MAPK cascade / response to UV / negative regulation of protein binding / energy homeostasis / vesicle-mediated transport / JNK cascade / cellular response to amino acid starvation / protein serine/threonine kinase binding / NRIF signals cell death from the nucleus / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / cellular response to reactive oxygen species / positive regulation of JNK cascade / FCERI mediated MAPK activation / cellular response to mechanical stimulus / regulation of circadian rhythm / mitochondrial membrane / peptidyl-serine phosphorylation / histone deacetylase binding / cellular senescence / Signaling by ALK fusions and activated point mutants / rhythmic process / MAPK cascade / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / regulation of protein localization / cellular response to lipopolysaccharide / cellular response to oxidative stress / response to oxidative stress / protein phosphatase binding / Oxidative Stress Induced Senescence / protein phosphorylation / positive regulation of apoptotic process / axon / protein serine kinase activity / neuronal cell body / protein serine/threonine kinase activity / synapse / positive regulation of gene expression / regulation of DNA-templated transcription / endoplasmic reticulum membrane / negative regulation of apoptotic process / perinuclear region of cytoplasm / enzyme binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
JIP1, SH3 domain / : / Mitogen-activated protein (MAP) kinase, JNK / Phosphotyrosine interaction domain (PTB/PID) / Phosphotyrosine interaction domain (PID) profile. / Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain / PTB/PI domain / Variant SH3 domain / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. ...JIP1, SH3 domain / : / Mitogen-activated protein (MAP) kinase, JNK / Phosphotyrosine interaction domain (PTB/PID) / Phosphotyrosine interaction domain (PID) profile. / Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain / PTB/PI domain / Variant SH3 domain / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Src homology 3 domains / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / PH-like domain superfamily / 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. / 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-1BK / Stress-activated protein kinase JNK / Mitogen-activated protein kinase 8 / C-Jun-amino-terminal kinase-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.152 Å
AuthorsKuglstatter, A. / Ghate, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole lead.
Authors: Palmer, W.S. / Alam, M. / Arzeno, H.B. / Chang, K.C. / Dunn, J.P. / Goldstein, D.M. / Gong, L. / Goyal, B. / Hermann, J.C. / Hogg, J.H. / Hsieh, G. / Jahangir, A. / Janson, C. / Jin, S. / ...Authors: Palmer, W.S. / Alam, M. / Arzeno, H.B. / Chang, K.C. / Dunn, J.P. / Goldstein, D.M. / Gong, L. / Goyal, B. / Hermann, J.C. / Hogg, J.H. / Hsieh, G. / Jahangir, A. / Janson, C. / Jin, S. / Ursula Kammlott, R. / Kuglstatter, A. / Lukacs, C. / Michoud, C. / Niu, L. / Reuter, D.C. / Shao, A. / Silva, T. / Trejo-Martin, T.A. / Stein, K. / Tan, Y.C. / Tivitmahaisoon, P. / Tran, P. / Wagner, P. / Weller, P. / Wu, S.Y.
History
DepositionNov 14, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 30, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 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 8
B: C-Jun-amino-terminal kinase-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3793
Polymers43,9342
Non-polymers4461
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-8 kcal/mol
Surface area16050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.438, 81.769, 82.502
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 / Mitogen-activated protein kinase 8 isoform JNK1 beta2 / Mitogen-activated protein kinase 8 / ...Mitogen-activated protein kinase 8 isoform JNK1 beta2 / Mitogen-activated protein kinase 8 / isoform CRA_d / cDNA FLJ77387 / highly similar to Homo sapiens mitogen-activated protein kinase 8 (MAPK8) / transcript variant 4 / mRNA


Mass: 42588.191 Da / Num. of mol.: 1 / Fragment: Residues 1-369
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK8, hCG_23734 / Production host: Escherichia coli (E. coli)
References: UniProt: A1L4K2, UniProt: P45983*PLUS, EC: 2.7.1.37
#2: Protein/peptide C-Jun-amino-terminal kinase-interacting protein 1 / JIP-1 / JNK-interacting protein 1 / Islet-brain 1 / IB-1 / JNK MAP kinase scaffold protein 1 / ...JIP-1 / JNK-interacting protein 1 / Islet-brain 1 / IB-1 / JNK MAP kinase scaffold protein 1 / Mitogen-activated protein kinase 8-interacting protein 1


Mass: 1345.612 Da / Num. of mol.: 1 / Fragment: Residues 157-167 / Source method: obtained synthetically / Details: Chemical synthesis / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UQF2
#3: Chemical ChemComp-1BK / trans-4-[(4-{4-[3-(methylsulfonyl)propoxy]-1H-indazol-1-yl}pyrimidin-2-yl)amino]cyclohexanol


Mass: 445.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N5O4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 46.98 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 20% PEG 3350, 0.2 M LiSO4, 0.1 M BIS-TRIS, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.15→58.12 Å / Num. obs: 21746 / % possible obs: 95.4 % / Redundancy: 6.4 % / Rsym value: 0.099 / Net I/σ(I): 16.6
Reflection shellResolution: 2.15→2.23 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 1.74 / Num. unique all: 1592 / Rsym value: 0.447 / % possible all: 71.3

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1UKH

1ukh


Resolution: 2.152→58.12 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.921 / SU B: 6.368 / SU ML: 0.167 / Cross valid method: THROUGHOUT / ESU R: 0.277 / ESU R Free: 0.22 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26898 1109 5.1 %RANDOM
Rwork0.2292 ---
obs0.23122 20592 95.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 48.425 Å2
Baniso -1Baniso -2Baniso -3
1--2.02 Å20 Å20 Å2
2--3.12 Å20 Å2
3----1.09 Å2
Refinement stepCycle: LAST / Resolution: 2.152→58.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2674 0 31 76 2781
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222766
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1261.9853738
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8345326
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.63324.309123
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.15115504
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1781515
X-RAY DIFFRACTIONr_chiral_restr0.0770.2412
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022047
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1910.21201
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3010.21878
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1290.2105
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2690.231
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1960.210
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5921.51706
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.01922682
X-RAY DIFFRACTIONr_scbond_it1.32231214
X-RAY DIFFRACTIONr_scangle_it2.1264.51056
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.152→2.208 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.337 57 -
Rwork0.285 1046 -
obs--67.34 %

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