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- PDB-4eh9: Human p38 MAP kinase in complex with NP-F11 and RL87 -

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Basic information

Entry
Database: PDB / ID: 4eh9
TitleHuman p38 MAP kinase in complex with NP-F11 and RL87
ComponentsMitogen-activated protein kinase 14
KeywordsTransferase/Transferase inhibitor / MAP Kinase Insert / Kinase-Ligand Complex / allosteric pocket / 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 / fatty acid oxidation / response to dietary excess / cellular response to lipoteichoic acid / response to muramyl dipeptide / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / 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 / positive regulation of erythrocyte differentiation / osteoclast 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 / cellular senescence / ADP signalling through P2Y purinoceptor 1 / 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-0OQ / N~4~-cyclopropyl-2-phenylquinazoline-4,7-diamine / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsOver, B. / Gruetter, C. / Waldmann, H. / Rauh, D.
CitationJournal: Nat Chem / Year: 2012
Title: Natural-product-derived fragments for fragment-based ligand discovery.
Authors: Over, B. / Wetzel, S. / Grutter, C. / Nakai, Y. / Renner, S. / Rauh, D. / Waldmann, H.
History
DepositionApr 2, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 5, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9083
Polymers41,2691
Non-polymers6392
Water1,09961
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.620, 74.920, 78.190
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 / Stress-activated protein kinase 2a / 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, SAPK2A / Plasmid: pGEX 6P-1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-IRG / N~4~-cyclopropyl-2-phenylquinazoline-4,7-diamine


Mass: 276.336 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16N4
#3: Chemical ChemComp-0OQ / (1R,5S)-3-[4-(trifluoromethyl)benzoyl]-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one


Mass: 362.346 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17F3N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 61 / 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: 2.33 Å3/Da / Density % sol: 47.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100 mM MES, 19-24% PEG 4000, pH 6.5, 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 14, 2012 / Details: Dynamical bendable mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→45 Å / Num. all: 22931 / Num. obs: 23132 / % possible obs: 99.1 % / Observed criterion σ(I): -3 / Redundancy: 3.66 % / Biso Wilson estimate: 49.085 Å2 / Rmerge(I) obs: 0.037 / Net I/σ(I): 18.94
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique obs% possible all
2.1-2.20.3913.4610949292398.4
2.2-2.30.274.939305244399
2.3-2.40.1966.467629205099.2
2.4-2.50.1547.866277173998.6
2.5-2.60.1139.865293149899.4
2.6-2.70.09112.644817129099.4
2.7-2.80.07715.254171109398.8
2.8-30.0618.956891181499.3
3-3.50.03727.1210354292099.5
3.5-40.02739.846220165699.6
4-50.02444.155830167099.3
5-60.02444.48268675099.7
6-100.02345.71278283299.4
100.02150.5281025398.4

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Processing

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

1zyj


Resolution: 2.1→41.74 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.9 / WRfactor Rfree: 0.2784 / WRfactor Rwork: 0.2307 / Occupancy max: 1 / Occupancy min: 0.9 / FOM work R set: 0.7775 / SU B: 6.26 / SU ML: 0.166 / SU R Cruickshank DPI: 0.2502 / SU Rfree: 0.2138 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.25 / ESU R Free: 0.214 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.28 1147 5 %RANDOM
Rwork0.2291 ---
obs0.2316 22930 99.1 %-
all-23132 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 74.93 Å2 / Biso mean: 44.3926 Å2 / Biso min: 21.15 Å2
Baniso -1Baniso -2Baniso -3
1-0.37 Å20 Å20 Å2
2---1.12 Å20 Å2
3---0.75 Å2
Refinement stepCycle: LAST / Resolution: 2.1→41.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2675 0 47 61 2783
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222788
X-RAY DIFFRACTIONr_angle_refined_deg1.2781.9843793
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4285330
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.05724.016127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.93815468
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1881517
X-RAY DIFFRACTIONr_chiral_restr0.0860.2424
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212099
X-RAY DIFFRACTIONr_mcbond_it0.7791.51670
X-RAY DIFFRACTIONr_mcangle_it1.45822704
X-RAY DIFFRACTIONr_scbond_it1.83931118
X-RAY DIFFRACTIONr_scangle_it3.0084.51086
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 83 -
Rwork0.29 1566 -
all-1649 -
obs--100 %

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