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- PDB-4y5h: Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Te... -

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Basic information

Entry
Database: PDB / ID: 4y5h
TitlePyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) inhibitors
ComponentsMitogen-activated protein kinase 10
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / JNK / MAP kinase / 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 / 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-519 / Mitogen-activated protein kinase 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.055 Å
AuthorsPark, H.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors.
Authors: Zheng, K. / Park, C.M. / Iqbal, S. / Hernandez, P. / Park, H. / LoGrasso, P.V. / Feng, Y.
History
DepositionFeb 11, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 6, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation

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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)42,6482
Polymers42,2621
Non-polymers3861
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.708, 71.813, 107.802
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: 42261.945 Da / Num. of mol.: 1 / Fragment: UNP residues 39-402
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-519 / 1-(trans-4-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}cyclohexyl)-3-propan-2-ylurea


Mass: 386.491 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H30N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.46 Å3/Da / Density % sol: 49.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: PEG 3350, ammonium tartrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 31, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.05→107.8 Å / Num. obs: 26485 / % possible obs: 99.3 % / Redundancy: 4.2 % / Net I/σ(I): 18.5

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementResolution: 2.055→24.036 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 34.81 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2852 1276 4.89 %
Rwork0.2362 --
obs0.2385 26115 98.01 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.055→24.036 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2827 0 28 1 2856
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072921
X-RAY DIFFRACTIONf_angle_d1.1253955
X-RAY DIFFRACTIONf_dihedral_angle_d17.4521104
X-RAY DIFFRACTIONf_chiral_restr0.045435
X-RAY DIFFRACTIONf_plane_restr0.005502
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.055-2.13720.34761390.34662758X-RAY DIFFRACTION100
2.1372-2.23440.35551540.32042691X-RAY DIFFRACTION98
2.2344-2.35210.43611310.33762456X-RAY DIFFRACTION89
2.3521-2.49930.34461560.28642776X-RAY DIFFRACTION100
2.4993-2.6920.35361400.28482789X-RAY DIFFRACTION100
2.692-2.96250.30611270.2732798X-RAY DIFFRACTION100
2.9625-3.39020.32851370.262836X-RAY DIFFRACTION100
3.3902-4.26740.24441470.20972818X-RAY DIFFRACTION99
4.2674-24.03780.22091450.17262917X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.2210.2473-0.20961.8809-0.77741.3825-0.1133-0.1117-0.0109-0.61850.00580.03990.0598-0.099-0.00730.48420.06530.00690.3764-0.0130.34486.5078-21.3135-42.0873
21.63450.2432-0.14280.6589-0.23251.91480.0780.084-0.01840.1202-0.1742-0.07710.06930.0743-0.00170.27840.0029-0.00940.32670.02330.354210.0294-24.6704-22.4323
30.6423-0.38230.46551.9149-0.31132.0896-0.0199-0.03420.03410.7848-0.01770.0022-0.3752-0.1116-0.00330.5235-0.0251-0.03290.32020.01430.31938.5272-18.4362-6.6113
41.00950.9238-0.19470.96910.09060.6126-0.1607-0.09740.007-0.0101-0.2836-0.8764-0.32850.4177-0.00160.5541-0.00320.03310.55450.10130.560618.262-14.8562-33.9472
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 45:147 )A45 - 147
2X-RAY DIFFRACTION2( CHAIN A AND RESID 148:222 )A148 - 222
3X-RAY DIFFRACTION3( CHAIN A AND RESID 223:359 )A223 - 359
4X-RAY DIFFRACTION4( CHAIN A AND RESID 360:400 )A360 - 400

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