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- PDB-8elc: Human JNK2 bound to covalent inhibitor YL2056 -

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Basic information

Entry
Database: PDB / ID: 8elc
TitleHuman JNK2 bound to covalent inhibitor YL2056
ComponentsMitogen-activated protein kinase 9
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / JNK2 / YLIU2056 / Kinase Inhibitor / Structure-Based Drug Design / TRANSFERASE / TRANSFERASE-Inhibitor complex / CELL CYCLE / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


protein localization to tricellular tight junction / JUN kinase activity / inflammatory response to wounding / positive regulation of macrophage derived foam cell differentiation / positive regulation of cytokine production involved in inflammatory response / positive regulation of podosome assembly / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / mitogen-activated protein kinase / JNK cascade ...protein localization to tricellular tight junction / JUN kinase activity / inflammatory response to wounding / positive regulation of macrophage derived foam cell differentiation / positive regulation of cytokine production involved in inflammatory response / positive regulation of podosome assembly / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / mitogen-activated protein kinase / JNK cascade / cellular response to cadmium ion / protein serine/threonine/tyrosine kinase activity / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of protein ubiquitination / apoptotic signaling pathway / positive regulation of apoptotic signaling pathway / FCERI mediated MAPK activation / Schaffer collateral - CA1 synapse / modulation of chemical synaptic transmission / regulation of circadian rhythm / cellular response to reactive oxygen species / cellular senescence / Signaling by ALK fusions and activated point mutants / rhythmic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / nuclear speck / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of gene expression / 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-Y56 / Mitogen-activated protein kinase 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.072 Å
AuthorsLi, L. / Gurbani, D. / Westover, K.D.
Funding support United States, 2items
OrganizationGrant numberCountry
Welch FoundationI-1829 United States
American Cancer SocietyRSG-18-039-01 United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1.
Authors: Lu, W. / Liu, Y. / Gao, Y. / Geng, Q. / Gurbani, D. / Li, L. / Ficarro, S.B. / Meyer, C.J. / Sinha, D. / You, I. / Tse, J. / He, Z. / Ji, W. / Che, J. / Kim, A.Y. / Yu, T. / Wen, K. / ...Authors: Lu, W. / Liu, Y. / Gao, Y. / Geng, Q. / Gurbani, D. / Li, L. / Ficarro, S.B. / Meyer, C.J. / Sinha, D. / You, I. / Tse, J. / He, Z. / Ji, W. / Che, J. / Kim, A.Y. / Yu, T. / Wen, K. / Anderson, K.C. / Marto, J.A. / Westover, K.D. / Zhang, T. / Gray, N.S.
History
DepositionSep 23, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,7842
Polymers48,1951
Non-polymers5891
Water1,31573
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.235, 65.761, 94.117
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Mitogen-activated protein kinase 9 / MAP kinase 9 / MAPK 9 / JNK-55 / Stress-activated protein kinase 1a / SAPK1a / Stress-activated ...MAP kinase 9 / MAPK 9 / JNK-55 / Stress-activated protein kinase 1a / SAPK1a / Stress-activated protein kinase JNK2 / c-Jun N-terminal kinase 2


Mass: 48194.965 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK9, JNK2, PRKM9, SAPK1A / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P45984, mitogen-activated protein kinase
#2: Chemical ChemComp-Y56 / 4-(dimethylamino)-N-{4-[(3S)-3-({4-[(8R)-2-phenylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}amino)pyrrolidine-1-carbonyl]phenyl}butanamide


Mass: 588.702 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H36N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / 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: 2.03 Å3/Da / Density % sol: 39.41 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Potassium phosphate dibasic, 20% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.072→47.06 Å / Num. obs: 24374 / % possible obs: 99.48 % / Redundancy: 2.2 % / Biso Wilson estimate: 39.65 Å2 / CC1/2: 0.52 / Net I/σ(I): 10.2
Reflection shellResolution: 2.072→2.146 Å / Num. unique obs: 23920 / CC1/2: 0.814 / % possible all: 97.58

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3npc

3npc


Resolution: 2.072→47.06 Å / SU ML: 0.2495 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.7387
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2603 1143 4.78 %
Rwork0.2078 22769 -
obs0.2103 23912 97.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 47.94 Å2
Refinement stepCycle: LAST / Resolution: 2.072→47.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2885 0 44 73 3002
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913002
X-RAY DIFFRACTIONf_angle_d1.06984070
X-RAY DIFFRACTIONf_chiral_restr0.0543445
X-RAY DIFFRACTIONf_plane_restr0.0071515
X-RAY DIFFRACTIONf_dihedral_angle_d11.6127396
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.072-2.170.34121200.28452722X-RAY DIFFRACTION94.89
2.17-2.280.30791370.26772751X-RAY DIFFRACTION95.79
2.28-2.420.28461520.24792764X-RAY DIFFRACTION96.68
2.42-2.610.31071580.22522809X-RAY DIFFRACTION97.7
2.61-2.870.26611290.21472878X-RAY DIFFRACTION98.62
2.87-3.290.25731500.21862852X-RAY DIFFRACTION98.23
3.29-4.140.25371510.18482938X-RAY DIFFRACTION99.65
4.14-47.060.23331460.1923055X-RAY DIFFRACTION98.95

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