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- PDB-2h96: Discovery of Potent, Highly Selective, and Orally Bioavailable Py... -

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Entry
Database: PDB / ID: 2h96
TitleDiscovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide C-jun NH2-terminal Kinase Inhibitors
Components
  • C-jun-amino-terminal kinase-interacting protein 1
  • Mitogen-activated protein kinase 8
KeywordsTRANSCRIPTION / JNK1 / C-JUN N-TERMINAL KINASE / PROTEIN KINASE JNK1 INHIBITORS / PYRIDINE CARBOXAMIDE INHIBITORS
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 / mitogen-activated protein kinase kinase binding / regulation of JNK cascade / mitogen-activated protein kinase kinase kinase binding / histone deacetylase regulator activity / NRAGE signals death through JNK / protein kinase inhibitor activity / 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 / dendritic growth cone / positive regulation of protein metabolic process / energy homeostasis / kinesin binding / peptidyl-threonine phosphorylation / mitogen-activated protein kinase / regulation of macroautophagy / response to mechanical stimulus / axonal growth cone / negative regulation of protein binding / response to UV / stress-activated MAPK cascade / NRIF signals cell death from the nucleus / vesicle-mediated transport / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / protein serine/threonine kinase binding / cellular response to amino acid starvation / cellular response to reactive oxygen species / FCERI mediated MAPK activation / positive regulation of JNK cascade / cellular response to mechanical stimulus / regulation of circadian rhythm / mitochondrial membrane / peptidyl-serine phosphorylation / histone deacetylase binding / Signaling by ALK fusions and activated point mutants / cellular senescence / rhythmic process / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / MAPK cascade / regulation of protein localization / cellular response to lipopolysaccharide / cellular response to oxidative stress / response to oxidative stress / Oxidative Stress Induced Senescence / protein phosphatase binding / protein phosphorylation / positive regulation of apoptotic process / axon / protein serine kinase activity / neuronal cell body / protein serine/threonine kinase activity / synapse / endoplasmic reticulum membrane / positive regulation of gene expression / negative regulation of apoptotic process / regulation of DNA-templated transcription / perinuclear region of cytoplasm / enzyme binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
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-893 / Mitogen-activated protein kinase 8 / C-Jun-amino-terminal kinase-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsAbad-Zapatero, C.
Citation
Journal: J.Med.Chem. / Year: 2006
Title: Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors.
Authors: Zhao, H. / Serby, M.D. / Xin, Z. / Szczepankiewicz, B.G. / Liu, M. / Kosogof, C. / Liu, B. / Nelson, L.T. / Johnson, E.F. / Wang, S. / Pederson, T. / Gum, R.J. / Clampit, J.E. / Haasch, D.L. ...Authors: Zhao, H. / Serby, M.D. / Xin, Z. / Szczepankiewicz, B.G. / Liu, M. / Kosogof, C. / Liu, B. / Nelson, L.T. / Johnson, E.F. / Wang, S. / Pederson, T. / Gum, R.J. / Clampit, J.E. / Haasch, D.L. / Abad-Zapatero, C. / Fry, E.H. / Rondinone, C. / Trevillyan, J.M. / Sham, H.L. / Liu, G.
#1: Journal: J.Med.Chem. / Year: 2006
Title: Aminopyridine-Based c-Jun N-Terminal Kinase Inhibitors with Cellular Activity and Minimal Cross-Kinase Activity.
Authors: Szczepankiewicz, B.G. / Kosogof, C. / Nelson, L.T. / Liu, G. / Liu, B. / Zhao, H. / Serby, M.D. / Xin, Z. / Liu, M. / Gum, R.J. / Haasch, D.L. / Wang, S. / Clampit, J.E. / Johnson, E.F. / ...Authors: Szczepankiewicz, B.G. / Kosogof, C. / Nelson, L.T. / Liu, G. / Liu, B. / Zhao, H. / Serby, M.D. / Xin, Z. / Liu, M. / Gum, R.J. / Haasch, D.L. / Wang, S. / Clampit, J.E. / Johnson, E.F. / Lubben, T.H. / Stashko, M.A. / Olejniczak, E.T. / Sun, C. / Dorwin, S.A. / Haskins, K. / Abad-Zapatero, C. / Fry, E.H. / Hutchins, C.W. / Sham, H.L. / Rondinone, C.M. / Trevillyan, J.M.
#2: Journal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Synthesis and SAR of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as novel, selective c-Jun N-terminal kinase inhibitors.
Authors: Liu, M. / Xin, Z. / Clampit, J.E. / Wang, S. / Gum, R.J. / Haasch, D.L. / Trevillyan, J.M. / Abad-Zapatero, C. / Fry, E.H. / Sham, H.L. / Liu, G.
History
DepositionJun 9, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 25, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Category: 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
Revision 1.4Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Remark 999SEQUENCE THE NATIVE, UNMUTATED SEQUENCE IS THE SAME AS THE P45983-2 ISOFORM. THE INTRODUCED ...SEQUENCE THE NATIVE, UNMUTATED SEQUENCE IS THE SAME AS THE P45983-2 ISOFORM. THE INTRODUCED MUTATIONS (THR183>GLU, TYR185>GLU) ARE INTENDED TO MIMIC THE ACTIVATED FORM OF THE KINASE UPON PHOSPHORYLATION OF THOSE TWO RESIDUES.

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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
F: C-jun-amino-terminal kinase-interacting protein 1
B: Mitogen-activated protein kinase 8
G: C-jun-amino-terminal kinase-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,78212
Polymers88,5304
Non-polymers1,2518
Water00
1
A: Mitogen-activated protein kinase 8
F: C-jun-amino-terminal kinase-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,8916
Polymers44,2652
Non-polymers6264
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-36 kcal/mol
Surface area17390 Å2
MethodPISA
2
B: Mitogen-activated protein kinase 8
G: C-jun-amino-terminal kinase-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,8916
Polymers44,2652
Non-polymers6264
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-39 kcal/mol
Surface area16480 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5370 Å2
ΔGint-96 kcal/mol
Surface area32400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)155.660, 155.660, 125.163
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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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: 42919.559 Da / Num. of mol.: 2 / Fragment: JNK1-(1-364)-6His / Mutation: T183E,Y183E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK8, JNK1, PRKM8 / Production host: Escherichia coli (E. coli)
References: UniProt: P45983, mitogen-activated protein kinase
#2: Protein/peptide C-jun-amino-terminal kinase-interacting protein 1 / JNK-interacting protein 1 / JIP-1 / JNK MAP kinase scaffold protein 1 / Islet-brain 1 / IB-1 / ...JNK-interacting protein 1 / JIP-1 / JNK MAP kinase scaffold protein 1 / Islet-brain 1 / IB-1 / Mitogen-activated protein kinase 8-interacting protein 1


Mass: 1345.612 Da / Num. of mol.: 2 / Fragment: PEPJIP1 PEPTIDE / Source method: obtained synthetically
Details: THE SEQUENCE IS FOUND NATURALLY IN HOMO SAPIENS (HUMAN).
References: UniProt: Q9UQF2
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-893 / 5-CYANO-N-(2,5-DIMETHOXYBENZYL)-6-ETHOXYPYRIDINE-2-CARBOXAMIDE / 5-CYANO-N-(2,5-DIMETHOXYBENZYL)-6-ETHOXYPICOLINAMIDE / 5-CYANO-N-(2,5-DIMETHOXYBENZYL)-6-ETHOXYPYRIDINE-2-CARBOXAMIDE


Mass: 341.361 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19N3O4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3

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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: 4.94 Å3/Da / Density % sol: 75.11 %
Crystal growpH: 6.2
Details: PROTEIN WAS PREINCUBATED WITH THE JIP1 PEPTIDE AT A 5X MOLAR EXCESS. PROTEIN CONCENTRATION 9- 12.6 MG/ML. HANGING DROPS CONSISTED OF 2UL PROTEIN PLUS 2 UL WELL SOLUTION. WELL SOLUTION:2.8-3. ...Details: PROTEIN WAS PREINCUBATED WITH THE JIP1 PEPTIDE AT A 5X MOLAR EXCESS. PROTEIN CONCENTRATION 9- 12.6 MG/ML. HANGING DROPS CONSISTED OF 2UL PROTEIN PLUS 2 UL WELL SOLUTION. WELL SOLUTION:2.8-3.1 M AMMONIUM SULFATE, 10- 14% GLYCEROL. FOR CO-CRYSTALLIZATION EXPERIMENT WITH THE COMPOUND, THE COMPOUND WAS DISSOLVED IN DMSO AT 100 MM CONCENTRATION. ALLOW TO INCUBATE FOR AT LEAST AN HOUR ON ICE. SOLUTION WAS SPUN FOR 5 MINUTES AT 2000G PRIOR TO SETTING UP FOR CRYSTALLIZATION, PH 6.2, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 277.0K, pH 6.20

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 18, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→20 Å / Num. all: 34786 / Num. obs: 31447 / % possible obs: 89.1 % / Observed criterion σ(I): 1 / Redundancy: 7.2 % / Biso Wilson estimate: 54.6 Å2 / Rmerge(I) obs: 0.094 / Rsym value: 0.094 / Net I/σ(I): 22.5
Reflection shellResolution: 3→3.11 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.754 / Mean I/σ(I) obs: 2.2 / Num. unique all: 3461 / Rsym value: 0.754 / % possible all: 99.5

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Processing

Software
NameClassification
ADSCdata collection
HKL-2000data reduction
CNXrefinement
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2G01

2g01


Resolution: 3→19.97 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 419658.34 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2
Details: Due to a feature in the refinement program, the structure was refined with OXT on one or more residues that is not the terminal residue of the sequence. In all these instances the OXT was ...Details: Due to a feature in the refinement program, the structure was refined with OXT on one or more residues that is not the terminal residue of the sequence. In all these instances the OXT was changed to N of the next residue. THE AUTHOR STATES: ALTHOUGH THE DATA IN THE HIGHEST RESOLUTION SHELL HAD POOR AGREEMENT FACTOR, IT WAS DECIDED TO INCLUDE THEM IN THE REFINEMENT BECAUSE THEY WERE RELATIVELY STRONG FOR THESE WEAK-DIFFRACTING CRYSTALS AND TO ADD MORE DATA GIVEN THE LARGE NUMBER OF ATOMS IN THE ASYMMETRIC UNIT. THE REFINEMENT OF INDIVIDUAL, RESTRAINT, B-FACTORS DROPPED BOTH THE R- AND THE R-FREE AND SO IT WAS CONSIDERED TO BE REASONABLE. HOWEVER, THE INDIVIDUAL VALUES REFLECT MORE TRENDS THAN INDIVIDUAL DIFFERENCES. THEY HAVE BEEN RETAINED IN THE ENTRY SPECIALLY TO SHOW DIFFERENCES BETWEEN THE SO4 IONS AND LIGANDS, AND AMONG DIFFERENT AMINO ACIDS IN THE CHAIN. THE DIFFERENCES AMONG INDIVDUAL ATOMS/GROUPS WITHIN EACH RESIDUE SHOULD BE CONSIDERED ONLY AS A TREND.
RfactorNum. reflection% reflectionSelection details
Rfree0.278 2801 9.9 %RANDOM
Rwork0.225 ---
all0.2433 31348 --
obs0.2433 28184 79.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 25.0512 Å2 / ksol: 0.29954 e/Å3
Displacement parametersBiso mean: 59.4 Å2
Baniso -1Baniso -2Baniso -3
1-8.92 Å229.47 Å20 Å2
2--8.92 Å20 Å2
3----17.83 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.48 Å0.37 Å
Luzzati d res low-6 Å
Luzzati sigma a0.56 Å0.45 Å
Refinement stepCycle: LAST / Resolution: 3→19.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5939 0 82 0 6021
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.9
X-RAY DIFFRACTIONc_improper_angle_d0.87
LS refinement shellResolution: 3→3.11 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.376 193 10.1 %
Rwork0.318 1713 -
obs-2137 54.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1ACCELRYS_CNX_TOPPAR:protein_rep.paramprotein.top
X-RAY DIFFRACTION2gcr.pargcr.top
X-RAY DIFFRACTION3ACCELRYS_CNX_TOPPAR:ion.paramACCELRYS_CNX_TOPPAR:ion.param
X-RAY DIFFRACTION4893.par893.top
X-RAY DIFFRACTION5so4.parso4.top

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