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- PDB-2gmx: Selective Aminopyridine-Based C-Jun N-terminal Kinase inhibitors ... -

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Basic information

Entry
Database: PDB / ID: 2gmx
TitleSelective Aminopyridine-Based C-Jun N-terminal Kinase inhibitors with cellular activity
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 / Aminopyridine-Based c-Jun N-Terminal Kinase 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 / 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 / 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 / protein kinase inhibitor activity / positive regulation of protein metabolic process / peptidyl-threonine phosphorylation / 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 / protein serine/threonine kinase binding / NRIF signals cell death from the nucleus / cellular response to amino acid starvation / 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 / response to oxidative stress / cellular 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-877 / 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.
Citation
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.
#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. / Liu, G.
History
DepositionApr 7, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 6, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: 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)89,78510
Polymers88,5304
Non-polymers1,2556
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)44,8935
Polymers44,2652
Non-polymers6273
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2360 Å2
ΔGint-34 kcal/mol
Surface area17120 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)44,8935
Polymers44,2652
Non-polymers6273
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2400 Å2
ΔGint-35 kcal/mol
Surface area16950 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6340 Å2
ΔGint-93 kcal/mol
Surface area32490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)150.786, 150.786, 118.660
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 / 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, 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-877 / N-(4-AMINO-5-CYANO-6-ETHOXYPYRIDIN-2-YL)-2-(4-BROMO-2,5-DIMETHOXYPHENYL)ACETAMIDE


Mass: 435.272 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19BrN4O4

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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: 72.02 %
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 2 uL well solution. Well solution:2.8-3.1 ...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

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
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: 3.5→20 Å / Num. all: 19198 / Num. obs: 17550 / % possible obs: 87.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 5.6 % / Biso Wilson estimate: 21.5 Å2 / Rmerge(I) obs: 0.078 / Rsym value: 0.078 / Net I/σ(I): 21
Reflection shellResolution: 3.5→3.62 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.385 / Mean I/σ(I) obs: 4.62 / Num. unique all: 1942 / Rsym value: 0.385 / % possible all: 99.3

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Processing

Software
NameVersionClassification
CNX2002refinement
ADSCdata collection
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2g01

2g01


Resolution: 3.5→19.91 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 337281.36 / 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
Rfree0.351 1658 10 %RANDOM
Rwork0.266 ---
all0.278 17547 --
obs0.278 16575 83.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 10 Å2 / ksol: 0.202359 e/Å3
Displacement parametersBiso mean: 56.4 Å2
Baniso -1Baniso -2Baniso -3
1--0.54 Å234.46 Å20 Å2
2---0.54 Å20 Å2
3---1.08 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.64 Å0.51 Å
Luzzati d res low-6 Å
Luzzati sigma a1.09 Å0.78 Å
Refinement stepCycle: LAST / Resolution: 3.5→19.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5892 0 74 0 5966
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.5
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.96
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 3.5→3.62 Å / Rfactor Rfree error: 0.04 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.438 119 10 %
Rwork0.365 1073 -
obs--60.8 %
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.param877.top
X-RAY DIFFRACTION4877.parso4.par
X-RAY DIFFRACTION5so4.par

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