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- PDB-4fa2: Human P38 alpha Mitogen-Activated Kinase In Complex With SB239063 -

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Basic information

Entry
Database: PDB / ID: 4fa2
TitleHuman P38 alpha Mitogen-Activated Kinase In Complex With SB239063
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase catalytic domain / 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 / CD163 mediating an anti-inflammatory response / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...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 / CD163 mediating an anti-inflammatory response / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / Platelet sensitization by LDL / positive regulation of muscle cell differentiation / 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 / Regulation of MITF-M-dependent genes involved in pigmentation / fatty acid oxidation / cellular response to lipoteichoic acid / response to dietary excess / response to muramyl dipeptide / MAP kinase kinase activity / JUN kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / MAP kinase activity / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / positive regulation of myoblast differentiation / vascular endothelial growth factor receptor signaling pathway / skeletal muscle tissue development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / p38MAPK events / striated muscle cell differentiation / positive regulation of brown fat cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / placenta development / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / 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 / response to insulin / NOD1/2 Signaling Pathway / cell morphogenesis / bone development / cellular response to virus / platelet activation / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / spindle pole / chemotaxis / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / peptidyl-serine phosphorylation / cellular senescence / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / angiogenesis / protein phosphatase binding / secretory granule lumen / 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 / nuclear speck / intracellular signal transduction / 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
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
BETA-MERCAPTOETHANOL / 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE / Chem-SB0 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsGrum-Tokars, V.L. / Minasov, G. / Anderson, W.F. / Watterson, D.M.
Funding support United States, 5items
OrganizationGrant numberCountry
Alzheimerss Drug Discovery Foundation (ADDF)261108 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)U01AG043415 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)R01AG031311 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS056051 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS093920 United States
CitationJournal: Plos One / Year: 2013
Title: Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction.
Authors: Watterson, D.M. / Grum-Tokars, V.L. / Roy, S.M. / Schavocky, J.P. / Bradaric, B.D. / Bachstetter, A.D. / Xing, B. / Dimayuga, E. / Saeed, F. / Zhang, H. / Staniszewski, A. / Pelletier, J.C. ...Authors: Watterson, D.M. / Grum-Tokars, V.L. / Roy, S.M. / Schavocky, J.P. / Bradaric, B.D. / Bachstetter, A.D. / Xing, B. / Dimayuga, E. / Saeed, F. / Zhang, H. / Staniszewski, A. / Pelletier, J.C. / Minasov, G. / Anderson, W.F. / Arancio, O. / Van Eldik, L.J.
History
DepositionMay 21, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 5, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 12, 2013Group: Database references
Revision 1.2Jul 24, 2013Group: Database references
Revision 1.3Jan 1, 2020Group: Author supporting evidence / Database references / Derived calculations
Category: pdbx_audit_support / struct_conn / struct_ref_seq_dif
Item: _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details
Revision 1.4Mar 26, 2025Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)44,7045
Polymers43,9561
Non-polymers7484
Water3,207178
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.113, 74.133, 77.770
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#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: 43955.906 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 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)pLysS
References: UniProt: Q16539, mitogen-activated protein kinase

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Non-polymers , 5 types, 182 molecules

#2: Chemical ChemComp-GG5 / 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE


Mass: 239.248 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H10FN3
#3: Chemical ChemComp-SB0 / trans-4-[4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)-1H-imidazol-1-yl]cyclohexanol


Mass: 368.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21FN4O2
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationN

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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: 2.14 Å3/Da / Density % sol: 42.39 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1M Ammonium Acetate, 0.1 M BIS-TRIS pH 5.5, 17% PEG 10000, VAPOR DIFFUSION, SITTING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 9, 2011 / Details: Beryllium lenses
RadiationMonochromator: DIAMOND / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. all: 26070 / Num. obs: 26070 / % possible obs: 99.9 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 7.3 % / Rmerge(I) obs: 0.059
Reflection shellResolution: 2→2.03 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 4.87 / Num. unique all: 1268 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.5.0102refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→29.81 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.949 / SU B: 7.563 / SU ML: 0.1 / Cross valid method: THROUGHOUT / ESU R: 0.177 / ESU R Free: 0.155 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21454 1323 5.1 %RANDOM
Rwork0.17218 ---
obs0.17423 24696 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.115 Å2
Baniso -1Baniso -2Baniso -3
1--1.45 Å20 Å20 Å2
2---0.87 Å2-0 Å2
3---2.33 Å2
Refinement stepCycle: LAST / Resolution: 2→29.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2736 0 53 178 2967
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0223009
X-RAY DIFFRACTIONr_bond_other_d0.0010.022028
X-RAY DIFFRACTIONr_angle_refined_deg1.3321.9814104
X-RAY DIFFRACTIONr_angle_other_deg0.82734955
X-RAY DIFFRACTIONr_dihedral_angle_1_deg2.8735368
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.78624.225142
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.815518
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9471519
X-RAY DIFFRACTIONr_chiral_restr0.0850.2451
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213375
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02614
X-RAY DIFFRACTIONr_mcbond_it1.1171.51791
X-RAY DIFFRACTIONr_mcbond_other0.3341.5706
X-RAY DIFFRACTIONr_mcangle_it1.93922925
X-RAY DIFFRACTIONr_scbond_it3.03231218
X-RAY DIFFRACTIONr_scangle_it4.5434.51179
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.25 90 -
Rwork0.182 1781 -
obs--98.79 %
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)
16.8935-0.23131.17424.4102-1.81814.9312-0.0415-0.5418-0.24120.26380.15940.5225-0.3259-0.2872-0.11790.1141-0.00140.0930.14480.08640.1835-16.17070.116621.5108
23.7686-0.94870.06022.4446-1.52252.39350.1044-0.0568-0.17520.1560.04880.2945-0.2245-0.1425-0.15320.09270.00320.0140.0220.01020.0399-6.24013.781914.2189
34.33010.8193-0.36813.1609-0.38812.24310.1025-0.1465-0.42420.1774-0.29190.03850.15490.02030.18940.0975-0.0050.010.05730.02950.08710.4329-4.206417.5032
44.45761.2969-0.14762.8715-0.13761.24630.1095-0.21860.41780.1681-0.140.1027-0.07180.07130.03040.0847-0.0132-0.00070.08750.03820.085520.164910.574318.8111
53.71890.18260.02341.84580.150.69020.0637-0.1099-0.1910.0519-0.098-0.38020.05060.25130.03430.12640.02810.01720.17070.07840.107324.2211.454814.7845
63.4045-0.8818-0.57897.9364-4.89514.8810.19880.4831-0.1329-0.4344-0.09520.32540.2165-0.0983-0.10360.13450.0619-0.03630.18020.02880.0471-8.33287.53472.6409
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 48
2X-RAY DIFFRACTION2A49 - 120
3X-RAY DIFFRACTION3A121 - 167
4X-RAY DIFFRACTION4A168 - 250
5X-RAY DIFFRACTION5A251 - 324
6X-RAY DIFFRACTION6A325 - 353

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