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Yorodumi- PDB-2h96: Discovery of Potent, Highly Selective, and Orally Bioavailable Py... -
+Open data
-Basic information
Entry | Database: PDB / ID: 2h96 | ||||||
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Title | Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide C-jun NH2-terminal Kinase Inhibitors | ||||||
Components |
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Keywords | TRANSCRIPTION / JNK1 / C-JUN N-TERMINAL KINASE / PROTEIN KINASE JNK1 INHIBITORS / PYRIDINE CARBOXAMIDE INHIBITORS | ||||||
Function / homology | Function and homology information positive regulation of cell killing / dentate gyrus mossy fiber / JUN phosphorylation / regulation of DNA replication origin binding / regulation of CD8-positive, alpha-beta T cell proliferation / : / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria ...positive regulation of cell killing / dentate gyrus mossy fiber / JUN phosphorylation / regulation of DNA replication origin binding / regulation of CD8-positive, alpha-beta T cell proliferation / : / 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 / negative regulation of JUN kinase activity / MAP-kinase scaffold activity / protein serine/threonine kinase binding / JUN kinase binding / positive regulation of cyclase activity / histone deacetylase regulator activity / positive regulation of NLRP3 inflammasome complex assembly / DSCAM interactions / NRAGE signals death through JNK / protein kinase inhibitor activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / kinesin binding / regulation of JNK cascade / regulation of macroautophagy / mitogen-activated protein kinase / negative regulation of intrinsic apoptotic signaling pathway / stress-activated MAPK cascade / response to mechanical stimulus / response to UV / JNK cascade / vesicle-mediated transport / cellular response to cadmium ion / cellular response to amino acid starvation / positive regulation of protein metabolic process / NRIF signals cell death from the nucleus / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / negative regulation of protein binding / mitochondrial membrane / FCERI mediated MAPK activation / positive regulation of JNK cascade / peptidyl-threonine phosphorylation / regulation of circadian rhythm / cellular response to reactive oxygen species / cellular response to mechanical stimulus / histone deacetylase binding / rhythmic process / regulation of protein localization / cellular senescence / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / cellular response to oxidative stress / protein phosphatase binding / peptidyl-serine phosphorylation / 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 / dendrite / neuronal cell body / synapse / endoplasmic reticulum membrane / positive regulation of gene expression / regulation of DNA-templated transcription / negative regulation of apoptotic process / perinuclear region of cytoplasm / enzyme binding / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å | ||||||
Authors | Abad-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 |
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Remark 999 | SEQUENCE 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. |
-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 2h96.cif.gz | 162.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb2h96.ent.gz | 129.6 KB | Display | PDB format |
PDBx/mmJSON format | 2h96.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/h9/2h96 ftp://data.pdbj.org/pub/pdb/validation_reports/h9/2h96 | HTTPS FTP |
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-Related structure data
Related structure data | 2g01S S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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3 |
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Unit cell |
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-Components
#1: Protein | 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 | 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 / #4: Chemical | #5: Chemical | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 4.94 Å3/Da / Density % sol: 75.11 % |
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Crystal grow | pH: 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 |
-Data collection
Diffraction | Mean temperature: 110 K |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 |
Detector | Type: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 18, 2004 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 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 shell | Resolution: 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 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 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.
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Solvent computation | Solvent model: FLAT MODEL / Bsol: 25.0512 Å2 / ksol: 0.29954 e/Å3 | |||||||||||||||||||||||||
Displacement parameters | Biso mean: 59.4 Å2
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Refine analyze |
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Refinement step | Cycle: LAST / Resolution: 3→19.97 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 3→3.11 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 10
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Xplor file |
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