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- PDB-3hll: Crystal Structure of Human p38alpha complexed with PH-797804 -

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Basic information

Entry
Database: PDB / ID: 3hll
TitleCrystal Structure of Human p38alpha complexed with PH-797804
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE / ATP-binding / Kinase / Nucleotide-binding / Nucleus / Phosphoprotein / Serine/threonine-protein kinase
Function / homology
Function and homology information


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 / DSCAM interactions / cartilage condensation ...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 / DSCAM interactions / cartilage condensation / cellular response to UV-B / Platelet sensitization by LDL / stress-activated protein kinase signaling cascade / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / positive regulation of muscle cell differentiation / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / glucose import / response to dietary excess / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / MAP kinase kinase activity / response to muramyl dipeptide / RHO GTPases Activate NADPH Oxidases / regulation of ossification / MAP kinase activity / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / signal transduction in response to DNA damage / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / positive regulation of cardiac muscle cell proliferation / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / placenta development / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / negative regulation of canonical Wnt signaling pathway / response to insulin / NOD1/2 Signaling Pathway / bone development / cell morphogenesis / platelet activation / osteoblast differentiation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / cellular senescence / cellular response to tumor necrosis factor / protein phosphatase binding / peptidyl-serine phosphorylation / angiogenesis / Oxidative Stress Induced Senescence / secretory granule lumen / cellular response to lipopolysaccharide / 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 / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / 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 / Serine/Threonine protein kinases, catalytic 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-I45 / Chem-I46 / HYPOPHOSPHITE / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.95 Å
AuthorsShieh, H.-S. / Williams, J.M. / Stegeman, R.A. / Kurumbail, R.G.
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 27, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 14, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance

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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)42,1414
Polymers41,3431
Non-polymers7983
Water3,657203
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.114, 74.645, 77.066
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 / MAPK14 / 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-I45 / 3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamide


Mass: 477.299 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H19BrF2N2O3
#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: Chemical ChemComp-PO2 / HYPOPHOSPHITE / Phosphinate


Mass: 62.973 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: O2P
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 203 / 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: 45.7 %
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-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 14, 2002 / Details: crystal monochromator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. all: 27860 / Num. obs: 27860 / % possible obs: 100 % / Observed criterion σ(F): -1.5 / Observed criterion σ(I): -3 / Redundancy: 6.9 % / Rmerge(I) obs: 0.053 / Rsym value: 0.053 / Net I/σ(I): 38.7
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 6 % / Rmerge(I) obs: 0.502 / Mean I/σ(I) obs: 2.9 / Rsym value: 0.502 / % possible all: 99.2

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.95→34.24 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.932 / SU B: 8.152 / SU ML: 0.126 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: restrained individual / Cross valid method: THROUGHOUT / ESU R: 0.196 / ESU R Free: 0.17 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2542 1416 5.1 %RANDOM
Rwork0.21727 ---
obs0.21909 26401 99.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.867 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å20 Å2
2---0.67 Å20 Å2
3---0.69 Å2
Refinement stepCycle: LAST / Resolution: 1.95→34.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2715 0 52 203 2970
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222840
X-RAY DIFFRACTIONr_bond_other_d0.0010.021889
X-RAY DIFFRACTIONr_angle_refined_deg1.31.9853856
X-RAY DIFFRACTIONr_angle_other_deg0.92634609
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5135337
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.01623.923130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.80215485
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2551518
X-RAY DIFFRACTIONr_chiral_restr0.0780.2425
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023191
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02560
X-RAY DIFFRACTIONr_nbd_refined0.2130.2615
X-RAY DIFFRACTIONr_nbd_other0.1910.21958
X-RAY DIFFRACTIONr_nbtor_refined0.1830.21394
X-RAY DIFFRACTIONr_nbtor_other0.0870.21407
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1540.2136
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.5350.217
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2870.232
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1240.210
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7451.51751
X-RAY DIFFRACTIONr_mcbond_other0.1261.5670
X-RAY DIFFRACTIONr_mcangle_it1.25522740
X-RAY DIFFRACTIONr_scbond_it1.60831269
X-RAY DIFFRACTIONr_scangle_it2.4374.51115
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2.003 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.334 105 -
Rwork0.264 1859 -
obs--97.42 %
Refinement TLS params.Method: refined / Origin x: 25.9658 Å / Origin y: 33.7909 Å / Origin z: 15.6192 Å
111213212223313233
T-0.0977 Å20.0084 Å2-0.0398 Å2--0.1594 Å2-0.0512 Å2---0.2066 Å2
L3.5197 °2-0.1704 °20.1212 °2-1.3879 °20.4892 °2--0.8058 °2
S-0.0072 Å °-0.3737 Å °0.0215 Å °0.1664 Å °-0.0166 Å °-0.1087 Å °0.075 Å °-0.0242 Å °0.0238 Å °

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