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- PDB-3hub: Human p38 MAP Kinase in Complex with Scios-469 -

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Basic information

Entry
Database: PDB / ID: 3hub
TitleHuman p38 MAP Kinase in Complex with Scios-469
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / DFG-in / Glycine-Rich Loop / Scios-469 / Alternative splicing / ATP-binding / Cytoplasm / Kinase / Nucleotide-binding / Nucleus / Phosphoprotein / Polymorphism / 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 / MAP kinase activity / RHO GTPases Activate NADPH Oxidases / 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 / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / 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 / DNA damage checkpoint signaling / positive regulation of D-glucose import / stem cell differentiation / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / negative regulation of inflammatory response to antigenic stimulus / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / NOD1/2 Signaling Pathway / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / glucose metabolic process / ADP signalling through P2Y purinoceptor 1 / chemotaxis / 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-469 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.25 Å
AuthorsGruetter, C. / Simard, J.R. / Rauh, D.
CitationJournal: J.Am.Chem.Soc. / Year: 2010
Title: Fluorophore labeling of the glycine-rich loop as a method of identifying inhibitors that bind to active and inactive kinase conformations.
Authors: Simard, J.R. / Getlik, M. / Grutter, C. / Schneider, R. / Wulfert, S. / Rauh, D.
History
DepositionJun 13, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
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 1.3Oct 13, 2021Group: Database references / Structure summary / Category: chem_comp / database_2 / struct_ref_seq_dif
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.4Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)42,0403
Polymers41,2351
Non-polymers8052
Water1,72996
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)68.010, 69.610, 74.440
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 / 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: 41234.973 Da / Num. of mol.: 1 / Mutation: C119S, C162S, A172C, F327L
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.: 1
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#3: Chemical ChemComp-469 / 2-(6-chloro-5-{[(2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazin-1-yl]carbonyl}-1-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide


Mass: 513.004 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H30ClFN4O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 2.14 Å3/Da / Density % sol: 42.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 100 mM MES, 20-30% PEG4000, 50 mM 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: 0.9791 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Oct 7, 2008 / Details: Dynamically bendable mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.25→40.72 Å / Num. all: 17335 / Num. obs: 17297 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 4.05 % / Biso Wilson estimate: 39.743 Å2 / Rmerge(I) obs: 0.062 / Net I/σ(I): 17.34
Reflection shellResolution: 2.25→2.35 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.418 / Mean I/σ(I) obs: 4.1 / Num. measured obs: 8542 / Num. unique all: 2086 / Num. unique obs: 2083 / % possible all: 99.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å40.72 Å
Translation2.5 Å40.72 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASER1.3.1phasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
XDSdata scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→40.72 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.879 / WRfactor Rfree: 0.284 / WRfactor Rwork: 0.209 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.773 / SU B: 8.414 / SU ML: 0.212 / SU R Cruickshank DPI: 0.366 / SU Rfree: 0.278 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.366 / ESU R Free: 0.278 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.292 865 5 %RANDOM
Rwork0.213 ---
obs0.217 17296 99.78 %-
all-17335 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 61.87 Å2 / Biso mean: 31.867 Å2 / Biso min: 10.8 Å2
Baniso -1Baniso -2Baniso -3
1-0.88 Å20 Å20 Å2
2---0.46 Å20 Å2
3----0.42 Å2
Refinement stepCycle: LAST / Resolution: 2.25→40.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2694 0 56 96 2846
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0222817
X-RAY DIFFRACTIONr_angle_refined_deg1.8421.9893829
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.815333
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.57124.062128
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.63515481
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.8581517
X-RAY DIFFRACTIONr_chiral_restr0.1120.2430
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022112
X-RAY DIFFRACTIONr_nbd_refined0.2210.21256
X-RAY DIFFRACTIONr_nbtor_refined0.3120.21898
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1910.2125
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2380.241
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1220.210
X-RAY DIFFRACTIONr_mcbond_it1.0721.51732
X-RAY DIFFRACTIONr_mcangle_it1.75322720
X-RAY DIFFRACTIONr_scbond_it2.5431272
X-RAY DIFFRACTIONr_scangle_it3.6954.51109
LS refinement shellResolution: 2.25→2.308 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.354 62 -
Rwork0.236 1184 -
all-1246 -
obs--100 %

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