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- PDB-3que: Human p38 MAP Kinase in Complex with Skepinone-L -

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Basic information

Entry
Database: PDB / ID: 3que
TitleHuman p38 MAP Kinase in Complex with Skepinone-L
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase Domain / Phosphate Transferase / Dibenzosuberone Derivative / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / D-glucose import / p38MAPK cascade / ERK/MAPK targets / response to dietary excess / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / Regulation of MITF-M-dependent genes involved in pigmentation / MAP kinase kinase activity / signal transduction in response to DNA damage / regulation of ossification / MAP kinase activity / cellular response to vascular endothelial growth factor stimulus / RHO GTPases Activate NADPH Oxidases / mitogen-activated protein kinase / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / negative regulation of hippo signaling / positive regulation of myoblast differentiation / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / p38MAPK events / positive regulation of brown fat cell differentiation / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / positive regulation of D-glucose import / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / response to insulin / bone development / cellular response to virus / platelet activation / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / glucose metabolic process / cell morphogenesis / positive regulation of reactive oxygen species metabolic process / chemotaxis / spindle pole / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / cellular senescence / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / secretory granule lumen / protein phosphatase binding / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / transcription by RNA polymerase II / cell surface receptor signaling pathway / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / glutamatergic synapse / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular region / nucleoplasm / ATP binding
Similarity search - Function
Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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-3FF / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.7 Å
AuthorsGruetter, C. / Mayer-Wrangowski, S. / Richters, A. / Rauh, D.
CitationJournal: Nat.Chem.Biol. / Year: 2012
Title: Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor.
Authors: Koeberle, S.C. / Romir, J. / Fischer, S. / Koeberle, A. / Schattel, V. / Albrecht, W. / Grutter, C. / Werz, O. / Rauh, D. / Stehle, T. / Laufer, S.A.
History
DepositionFeb 23, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 18, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2013Group: Database references
Revision 1.2Jul 29, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.name ..._chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _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 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,2794
Polymers41,2691
Non-polymers1,0103
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.408, 74.016, 77.470
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 14 / MAP kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID- ...MAP kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-binding protein / CSBP / MAP kinase MXI2 / MAX-interacting protein 2 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / SAPK2A


Mass: 41269.055 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2 / Plasmid: pGEX 6P-1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#3: Chemical ChemComp-3FF / 2-[(2,4-difluorophenyl)amino]-7-{[(2R)-2,3-dihydroxypropyl]oxy}-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one


Mass: 425.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21F2NO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

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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: 2.27 Å3/Da / Density % sol: 45.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 100mM MES, 20-30% PEG 4000, 50mM n-BOG, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 15, 2011 / Details: Dynamic bendable mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→45 Å / Num. all: 10812 / Num. obs: 10793 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 5.73 % / Biso Wilson estimate: 48.255 Å2 / Rmerge F obs: 0.104 / Rmerge(I) obs: 0.082 / Rrim(I) all: 0.09 / Net I/σ(I): 18.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Redundancy (%)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique allNum. unique obsRrim(I) all% possible all
2.7-2.860.4580.4964.1566201104110411040.543100
2.8-2.90.370.434.8956339529490.47199.7
2.9-30.30.3346.0147688268250.36699.9
3-3.620.1480.16311.4519461333733350.17999.9
3.62-4.420.0540.0625.4511360201620100.06799.7
4.42-6.20.0330.04234.248950160415990.04699.7
6.2-80.0280.03536.9726365025020.039100
8-120.0150.02157.1316783183180.023100
12-160.0140.01962.1638985840.02298.8
160.0170.01656.9629368670.01998.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 42.24 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.7 Å49.98 Å
Translation2.7 Å49.98 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
XDSdata scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ZYJ

1zyj


Resolution: 2.7→45 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.852 / WRfactor Rfree: 0.2805 / WRfactor Rwork: 0.2008 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.7466 / SU B: 17.286 / SU ML: 0.348 / SU Rfree: 0.4624 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.351 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3109 863 8 %RANDOM
Rwork0.2225 ---
obs0.2295 10790 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 71.05 Å2 / Biso mean: 40.7576 Å2 / Biso min: 17.73 Å2
Baniso -1Baniso -2Baniso -3
1-0.65 Å20 Å20 Å2
2---0.53 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 2.7→45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2764 0 71 14 2849
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0222903
X-RAY DIFFRACTIONr_angle_refined_deg1.6341.9933941
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9475341
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.95123.835133
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.22515490
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.381519
X-RAY DIFFRACTIONr_chiral_restr0.1020.2445
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212167
X-RAY DIFFRACTIONr_mcbond_it0.8061.51717
X-RAY DIFFRACTIONr_mcangle_it1.53622785
X-RAY DIFFRACTIONr_scbond_it2.0131186
X-RAY DIFFRACTIONr_scangle_it3.4514.51156
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.443 64 -
Rwork0.309 735 -
all-799 -
obs--100 %

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