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

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Basic information

Entry
Database: PDB / ID: 7ksj
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 / rhythmic process / cellular senescence / Oxidative Stress Induced Senescence / protein phosphorylation / protein serine kinase activity / signal transduction / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
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-X3Y / Mitogen-activated protein kinase 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 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)53,0852
Polymers52,6491
Non-polymers4361
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.451, 71.237, 107.804
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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-X3Y / 4-(4-{[(2-chloro-6-fluorophenyl)carbamoyl]amino}-1H-pyrazol-1-yl)-N-(oxetan-3-yl)thiophene-2-carboxamide


Mass: 435.860 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15ClFN5O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 1.88 Å3/Da / Density % sol: 34.44 %
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: 2.06→53.873 Å / Num. obs: 23626 / % possible obs: 93.7 % / Redundancy: 4.2 % / CC1/2: 0.999 / Net I/σ(I): 12.7
Reflection shellResolution: 2.06→2.095 Å / Mean I/σ(I) obs: 2.6 / Num. unique obs: 1199 / CC1/2: 0.94

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Processing

Software
NameVersionClassification
BUSTER2.10.3 (19-MAR-2020)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1JNK

1jnk


Resolution: 2.06→41.71 Å / Cor.coef. Fo:Fc: 0.887 / Cor.coef. Fo:Fc free: 0.847 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.355 / SU Rfree Blow DPI: 0.261
RfactorNum. reflection% reflectionSelection details
Rfree0.2917 978 5 %RANDOM
Rwork0.23 ---
obs0.2331 19550 77.6 %-
Displacement parametersBiso max: 124.23 Å2 / Biso mean: 56.77 Å2 / Biso min: 4.62 Å2
Baniso -1Baniso -2Baniso -3
1--3.3612 Å20 Å20 Å2
2--1.0619 Å20 Å2
3---2.2993 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.06→41.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2800 0 29 189 3018
Biso mean--35.71 31.34 -
Num. residues----346
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1682SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes880HARMONIC5
X-RAY DIFFRACTIONt_it2896HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion366SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4332SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5723HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg10375HARMONIC20.94
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion15.9
LS refinement shellResolution: 2.06→2.09 Å / Rfactor Rfree error: 0 / Total num. of bins used: 49
RfactorNum. reflection% reflection
Rfree0.2587 21 5.15 %
Rwork0.2715 387 -
all0.2708 408 -
obs--41.73 %
Refinement TLS params.Method: refined / Origin x: 16.3545 Å / Origin y: 15.3584 Å / Origin z: 23.5588 Å
111213212223313233
T0.2422 Å20.0244 Å2-0.0826 Å2--0.1516 Å2-0.0599 Å2---0.0983 Å2
L0 °2-0.4397 °2-0.0053 °2-3.2371 °21.1164 °2--2.4179 °2
S-0.0033 Å °-0.0244 Å °-0.0441 Å °0.0429 Å °-0.2713 Å °0.4291 Å °-0.3664 Å °-0.1506 Å °0.2746 Å °
Refinement TLS groupSelection details: { A|* }

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