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- PDB-2no3: Novel 4-anilinopyrimidines as potent JNK1 Inhibitors -

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Basic information

Entry
Database: PDB / ID: 2no3
TitleNovel 4-anilinopyrimidines as potent JNK1 Inhibitors
Components
  • C-JUN-AMINO-TERMINAL KINASE-INTERACTING protein 1
  • Mitogen-activated protein kinase 8
KeywordsSIGNALING PROTEIN/INHIBITOR / JNK1 / C-JUN N-TERMINAL KINASE / JNK1 INHIBITORS / ANILINOPYRIMIDINES JNK1 INHIBITORS / SIGNALING PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


JUN phosphorylation / positive regulation of cell killing / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / positive regulation of establishment of protein localization to mitochondrion / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity ...JUN phosphorylation / positive regulation of cell killing / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / positive regulation of establishment of protein localization to mitochondrion / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / positive regulation of cyclase activity / histone deacetylase regulator activity / NRAGE signals death through JNK / positive regulation of NLRP3 inflammasome complex assembly / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / mitogen-activated protein kinase / regulation of macroautophagy / response to mechanical stimulus / response to UV / protein serine/threonine kinase binding / stress-activated MAPK cascade / energy homeostasis / JNK cascade / positive regulation of protein metabolic process / cellular response to cadmium ion / 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 / peptidyl-threonine phosphorylation / FCERI mediated MAPK activation / regulation of circadian rhythm / histone deacetylase binding / cellular response to mechanical stimulus / cellular response to reactive oxygen species / cellular senescence / rhythmic process / Signaling by ALK fusions and activated point mutants / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / regulation of protein localization / cellular response to oxidative stress / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / Oxidative Stress Induced Senescence / response to oxidative stress / positive regulation of apoptotic process / protein phosphorylation / axon / 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. ...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-859 / Mitogen-activated protein kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsAbad-Zapatero, C.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Authors: Liu, M. / Wang, S. / Clampit, J.E. / Gum, R.J. / Haasch, D.L. / Rondinone, C.M. / Trevillyan, J.M. / Abad-Zapatero, C. / Fry, E.H. / Sham, H.L. / Liu, G.
#1: 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.
#2: Journal: J.Med.Chem. / Year: 2006
Title: Selective aminopyridine-based C-Jun N-terminal kinase inhibitors with cellular activiy
Authors: Szczepankiewicz, B.G. / Kosogof, C. / Nelson, L.T.J. / Liu, G. / Zhao, H. / Serby, M.D. / Xin, Z. / Liu, B. / Gum, R.J. / Haasch, D.
#3: 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. / Gum, R.J. / Clampit, J.E. / Haasch, D.L.
History
DepositionOct 24, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Oct 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 1.5Aug 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

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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)89,55710
Polymers88,5304
Non-polymers1,0276
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)44,7795
Polymers44,2652
Non-polymers5133
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2280 Å2
ΔGint-43 kcal/mol
Surface area16770 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)44,7795
Polymers44,2652
Non-polymers5133
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2410 Å2
ΔGint-39 kcal/mol
Surface area17210 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6040 Å2
ΔGint-103 kcal/mol
Surface area32630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)157.201, 157.201, 123.362
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 residues 1-364 / Mutation: T183E, Y183E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK8, JNK1, PRKM8 / Plasmid: PET28A / 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
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-859 / 2-({2-[(3-HYDROXYPHENYL)AMINO]PYRIMIDIN-4-YL}AMINO)BENZAMIDE


Mass: 321.333 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H15N5O2

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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: 4.97 Å3/Da / Density % sol: 75.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion / 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 6.20, VAPOR DIFFUSION, temperature 277.0K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jan 6, 2005 / Details: Osmic Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3.2→20 Å / Num. all: 28588 / Num. obs: 27814 / % possible obs: 94.5 % / Observed criterion σ(I): 1 / Redundancy: 5.6 % / Biso Wilson estimate: 36.8 Å2 / Rmerge(I) obs: 0.083 / Rsym value: 0.083 / Net I/σ(I): 15.3
Reflection shellResolution: 3.2→3.31 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.454 / Mean I/σ(I) obs: 1.6 / Num. unique all: 2866 / Rsym value: 0.812 / % possible all: 98.3

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Processing

Software
NameVersionClassification
CNX2002refinement
MAR345CCDdata collection
HKL-2000data reduction
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: entry 2h96

2h96


Resolution: 3.2→19.98 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 162862.68 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.276 2180 9.9 %RANDOM
Rwork0.206 ---
all0.2332 ---
obs0.2332 22039 75.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 24.1807 Å2 / ksol: 0.224291 e/Å3
Displacement parametersBiso mean: 65.1 Å2
Baniso -1Baniso -2Baniso -3
1-7.93 Å222.73 Å20 Å2
2--7.93 Å20 Å2
3----15.87 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.48 Å0.35 Å
Luzzati d res low-8 Å
Luzzati sigma a0.44 Å0.34 Å
Refinement stepCycle: LAST / Resolution: 3.2→19.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5897 0 68 0 5965
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.3
X-RAY DIFFRACTIONc_improper_angle_d0.83
LS refinement shellResolution: 3.2→3.31 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.335 153 11.6 %
Rwork0.278 1163 -
obs-1564 45.3 %
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 DIFFRACTION4859.par859.top
X-RAY DIFFRACTION5so4.parso4.top

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