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- PDB-2g01: Pyrazoloquinolones as Novel, Selective JNK1 inhibitors -

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Basic information

Entry
Database: PDB / ID: 2g01
TitlePyrazoloquinolones as Novel, Selective JNK1 inhibitors
Components
  • C-jun-amino-terminal kinase-interacting protein 1
  • Mitogen-activated protein kinase 8
KeywordsTRANSFERASE / JNK1 / c-jun N-Terminal Kinase / Protein Kinase JNK1 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 / JUN kinase activity ...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 / 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 / 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-73Q / 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: 3.5 Å
AuthorsAbad-Zapatero, C.
CitationJournal: 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
DepositionFeb 10, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Mar 14, 2018Group: Database references / Category: struct_ref_seq_dif / Item: _struct_ref_seq_dif.details
Revision 1.4Aug 30, 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
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)89,44210
Polymers88,5304
Non-polymers9126
Water0
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)44,7215
Polymers44,2652
Non-polymers4563
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2090 Å2
ΔGint-39 kcal/mol
Surface area16950 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)44,7215
Polymers44,2652
Non-polymers4563
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2210 Å2
ΔGint-37 kcal/mol
Surface area16980 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5780 Å2
ΔGint-100 kcal/mol
Surface area32440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)150.622, 150.622, 118.996
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, Y185E
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, EC: 2.7.1.37
#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 / Source method: obtained synthetically
Details: The sequence is found naturally in Homo sapiens (human).
References: UniProt: Q9UQF2
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-73Q / 6-CHLORO-9-HYDROXY-1,3-DIMETHYL-1,9-DIHYDRO-4H-PYRAZOLO[3,4-B]QUINOLIN-4-ONE


Mass: 263.680 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H10ClN3O2

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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: 4.4 Å3/Da / Density % sol: 72.04 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / 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 2uL well solution over 1 mL of well ...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 2uL well solution over 1 mL of well solution. Well solution: 2.8-3.1 M Ammonium Sulfate, 10-14% glycerol. For Co-crystallization experiment 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

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 18, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 3.5→20 Å / Num. all: 19322 / Num. obs: 15793 / % possible obs: 81.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 5.8 % / Biso Wilson estimate: 46.2 Å2 / Rmerge(I) obs: 0.065 / Rsym value: 0.065 / Net I/σ(I): 27.9
Reflection shellResolution: 3.5→3.62 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.365 / Mean I/σ(I) obs: 2.6 / Num. unique all: 1859 / Rsym value: 0.365 / % possible all: 63.7

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Processing

Software
NameVersionClassification
CNX2002refinement
SDMSdata reduction
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1jnk, JNK3 KINASE

1jnk


Resolution: 3.5→19.89 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 318422.57 / Data cutoff low absF: 0 / Isotropic thermal model: GROUP / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.354 1526 9.8 %RANDOM
Rwork0.283 ---
all0.296 19322 --
obs0.286 15493 77.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 10 Å2 / ksol: 0.184616 e/Å3
Displacement parametersBiso mean: 85.1 Å2
Baniso -1Baniso -2Baniso -3
1--8.5 Å227.59 Å20 Å2
2---8.5 Å20 Å2
3---17 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.65 Å0.55 Å
Luzzati d res low-6 Å
Luzzati sigma a1.36 Å0.99 Å
Refinement stepCycle: LAST / Resolution: 3.5→19.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5862 0 56 0 5918
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.8
X-RAY DIFFRACTIONc_improper_angle_d0.99
LS refinement shellResolution: 3.5→3.62 Å / Rfactor Rfree error: 0.047 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.447 92 9.9 %
Rwork0.472 840 -
obs--47.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1ACCELRYS_CNX_TOPPAR:protein_rep.paramprotein.top
X-RAY DIFFRACTION2ACCELRYS_CNX_TOPPAR:water_rep.paramion.top
X-RAY DIFFRACTION3ACCELRYS_CNX_TOPPAR:ion.param737.top
X-RAY DIFFRACTION4737.parso4.par
X-RAY DIFFRACTION5so4.par

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