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- PDB-7ksk: Thiophenyl-Pyrazolourea Derivatives as Potent, Brian Penetrant, O... -

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Basic information

Entry
Database: PDB / ID: 7ksk
TitleThiophenyl-Pyrazolourea Derivatives as Potent, Brian Penetrant, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors
ComponentsMitogen-activated protein kinase 10
KeywordsTRANSFERASE/Inhibitor / JNK3 / Kinase Inhibitor / Alzheimer Disease / Pyrazolourea / Neurodegeneration / TRANSFERASE / TRANSFERASE-Inhibitor complex
Function / homology
Function and homology information


JUN kinase activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / MAP kinase kinase activity / response to light stimulus / mitogen-activated protein kinase / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / FCERI mediated MAPK activation / regulation of circadian rhythm ...JUN kinase activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / MAP kinase kinase activity / response to light stimulus / mitogen-activated protein kinase / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / FCERI mediated MAPK activation / regulation of circadian rhythm / cellular senescence / rhythmic process / Oxidative Stress Induced Senescence / protein phosphorylation / protein serine kinase activity / signal transduction / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Mitogen-activated protein (MAP) kinase, JNK / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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
Similarity search - Domain/homology
Chem-X3V / Mitogen-activated protein kinase 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsPark, H.
Funding support1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors.
Authors: Feng, Y. / Park, H. / Bauer, L. / Ryu, J.C. / Yoon, S.O.
History
DepositionNov 23, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0672
Polymers52,6491
Non-polymers4181
Water95553
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.137, 71.224, 107.599
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Mitogen-activated protein kinase 10 / MAPK 10 / MAP kinase p49 3F12 / Stress-activated protein kinase 1b / SAPK1b / Stress-activated ...MAPK 10 / MAP kinase p49 3F12 / Stress-activated protein kinase 1b / SAPK1b / Stress-activated protein kinase JNK3 / c-Jun N-terminal kinase 3


Mass: 52649.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK10, JNK3, JNK3A, PRKM10, SAPK1B / Production host: Escherichia coli (E. coli)
References: UniProt: P53779, mitogen-activated protein kinase
#2: Chemical ChemComp-X3V / 4-(4-{[(2-chlorophenyl)carbamoyl]amino}-1H-pyrazol-1-yl)-N-(oxetan-3-yl)thiophene-2-carboxamide


Mass: 417.869 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16ClN5O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.9 Å3/Da / Density % sol: 35.17 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / Details: 0.2 M ammonium tartrate pH 7.0, 20 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Sep 21, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.836→53.8 Å / Num. obs: 31286 / % possible obs: 87.4 % / Redundancy: 4.2 % / CC1/2: 0.999 / Net I/σ(I): 17.7
Reflection shellResolution: 1.836→1.867 Å / Num. unique obs: 1775 / CC1/2: 0.859

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Processing

Software
NameVersionClassification
PHENIXDEV_3965refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1JNK

1jnk


Resolution: 1.84→53.8 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 38.11 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.29 1558 5.01 %
Rwork0.247 --
obs0.249 31116 86.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 50.18 Å2
Refinement stepCycle: LAST / Resolution: 1.84→53.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2716 0 28 53 2797
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.84-1.870.4668950.41841979X-RAY DIFFRACTION96
1.9-1.960.4971630.42862715X-RAY DIFFRACTION90
1.96-2.040.34581540.34083001X-RAY DIFFRACTION98
2.04-2.130.40581460.3142881X-RAY DIFFRACTION94
2.13-2.250.36041530.28032988X-RAY DIFFRACTION98
2.25-2.390.27651710.27682951X-RAY DIFFRACTION96
2.39-2.570.3011380.24513004X-RAY DIFFRACTION98
2.57-2.830.2968950.25821545X-RAY DIFFRACTION50
2.83-3.240.28451610.25283063X-RAY DIFFRACTION98
3.24-4.080.29831130.21452297X-RAY DIFFRACTION73
4.08-53.80.21981690.19663134X-RAY DIFFRACTION95

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