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- PDB-3hl7: Crystal Structure of Human p38alpha complexed with SD-0006 -

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Basic information

Entry
Database: PDB / ID: 3hl7
TitleCrystal Structure of Human p38alpha complexed with SD-0006
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / ATP-binding / Kinase / Nucleotide-binding / Nucleus / Phosphoprotein / Serine/threonine-protein kinase
Function / homology
Function and homology information


stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / positive regulation of myoblast fusion / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / D-glucose import / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / p38MAPK cascade / Regulation of MITF-M-dependent genes involved in pigmentation / fatty acid oxidation / MAP kinase kinase activity / cellular response to lipoteichoic acid / response to muramyl dipeptide / response to dietary excess / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / positive regulation of erythrocyte differentiation / osteoclast differentiation / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / positive regulation of D-glucose import / stem cell differentiation / cellular response to ionizing radiation / negative regulation of inflammatory response to antigenic stimulus / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / chemotaxis / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / angiogenesis / 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 / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / glutamatergic synapse / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / apoptotic process / 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. / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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. / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-I46 / Chem-I47 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.88 Å
AuthorsShieh, H.-S. / Kurumbail, R.G. / Stegeman, R.A. / Williams, J.M.
CitationJournal: Biochemistry / Year: 2009
Title: Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804.
Authors: Xing, L. / Shieh, H.S. / Selness, S.R. / Devraj, R.V. / Walker, J.K. / Devadas, B. / Hope, H.R. / Compton, R.P. / Schindler, J.F. / Hirsch, J.L. / Benson, A.G. / Kurumbail, R.G. / Stegeman, ...Authors: Xing, L. / Shieh, H.S. / Selness, S.R. / Devraj, R.V. / Walker, J.K. / Devadas, B. / Hope, H.R. / Compton, R.P. / Schindler, J.F. / Hirsch, J.L. / Benson, A.G. / Kurumbail, R.G. / Stegeman, R.A. / Williams, J.M. / Broadus, R.M. / Walden, Z. / Monahan, J.B.
History
DepositionMay 26, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 14, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)41,9983
Polymers41,3431
Non-polymers6552
Water4,666259
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.088, 74.525, 77.587
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 14 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti- ...Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-binding protein / CSBP / MAX-interacting protein 2 / MAP kinase MXI2 / SAPK2A


Mass: 41343.195 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSBP, CSBP1, CSBP2, CSPB1, MAPK14, MXI2, THP-1 / Plasmid: pGEX4T-1 / Production host: Escherichia coli (E. coli) / Strain (production host): DH10B
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-I47 / 2-{4-[5-(4-chlorophenyl)-4-pyrimidin-4-yl-1H-pyrazol-3-yl]piperidin-1-yl}-2-oxoethanol


Mass: 397.858 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20ClN5O2
#3: Chemical ChemComp-I46 / 2-fluoro-4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine


Mass: 257.238 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H9F2N3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 259 / 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: 2.28 Å3/Da / Density % sol: 45.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 9
Details: 20-30% PEG3000, 10 mM CaCl2, 50 mM CHES, pH 9.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Apr 5, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.88→40 Å / Num. all: 30715 / Num. obs: 30175 / % possible obs: 100 % / Observed criterion σ(F): -1.5 / Observed criterion σ(I): -3 / Redundancy: 6.5 % / Biso Wilson estimate: 28.3 Å2 / Rmerge(I) obs: 0.054 / Rsym value: 0.054 / Net I/σ(I): 34.6
Reflection shellResolution: 1.88→1.97 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.454 / Mean I/σ(I) obs: 2.5 / Num. unique all: 2405 / Rsym value: 0.454 / % possible all: 77.5

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Processing

Software
NameVersionClassification
HKL-2000data collection
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.88→24.84 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.941 / SU B: 7.017 / SU ML: 0.109 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: restrained individual isotropic / Cross valid method: THROUGHOUT / ESU R: 0.16 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22825 1547 5 %RANDOM
Rwork0.19858 ---
obs0.20006 29122 98.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.233 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20 Å2
2---1.19 Å20 Å2
3---1.18 Å2
Refinement stepCycle: LAST / Resolution: 1.88→24.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2698 0 47 259 3004
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222813
X-RAY DIFFRACTIONr_bond_other_d0.0010.021865
X-RAY DIFFRACTIONr_angle_refined_deg1.2851.9823821
X-RAY DIFFRACTIONr_angle_other_deg0.89834553
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3395334
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.93524.141128
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.68415478
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7651516
X-RAY DIFFRACTIONr_chiral_restr0.0760.2423
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023147
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02550
X-RAY DIFFRACTIONr_nbd_refined0.2080.2649
X-RAY DIFFRACTIONr_nbd_other0.1880.21953
X-RAY DIFFRACTIONr_nbtor_refined0.1880.21389
X-RAY DIFFRACTIONr_nbtor_other0.0890.21406
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.170.2186
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1090.216
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2080.241
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1290.211
X-RAY DIFFRACTIONr_mcbond_it0.7311.51713
X-RAY DIFFRACTIONr_mcbond_other0.1351.5671
X-RAY DIFFRACTIONr_mcangle_it1.22922722
X-RAY DIFFRACTIONr_scbond_it1.6631229
X-RAY DIFFRACTIONr_scangle_it2.5224.51099
LS refinement shellResolution: 1.88→1.933 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 88 -
Rwork0.245 1780 -
obs--81.75 %
Refinement TLS params.Method: refined / Origin x: 25.8924 Å / Origin y: 33.8746 Å / Origin z: 15.6439 Å
111213212223313233
T-0.1066 Å20.0204 Å2-0.0365 Å2--0.1878 Å2-0.0363 Å2---0.2379 Å2
L3.5555 °20.0056 °2-0.2605 °2-1.4505 °20.464 °2--0.9331 °2
S0.0126 Å °-0.1545 Å °-0.0092 Å °0.1142 Å °-0.0361 Å °-0.0817 Å °0.0352 Å °-0.0249 Å °0.0235 Å °

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