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- PDB-1wbs: Identification of novel p38 alpha MAP Kinase inhibitors using fra... -

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Basic information

Entry
Database: PDB / ID: 1wbs
TitleIdentification of novel p38 alpha MAP Kinase inhibitors using fragment-based lead generation.
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 14
KeywordsTRANSFERASE / P38 / MAP KINASE / INHIBITOR STRUCTURE / ALTERNATIVE SPLICING / ATP-BINDING / NUCLEAR PROTEIN / PHOSPHORYLATION / 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 / 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-LI2 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.8 Å
AuthorsTickle, J. / Cleasby, A. / Devine, L.A. / Jhoti, H.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Identification of Novel P38Alpha Map Kinase Inhibitors Using Fragment-Based Lead Generation.
Authors: Gill, A.L. / Frederickson, M. / Cleasby, A. / Woodhead, S.J. / Carr, M.G. / Woodhead, A.J. / Walker, M.T. / Congreve, M.S. / Devine, L.A. / Tisi, D. / O'Reilly, M. / Seavers, L.C. / Davis, D. ...Authors: Gill, A.L. / Frederickson, M. / Cleasby, A. / Woodhead, S.J. / Carr, M.G. / Woodhead, A.J. / Walker, M.T. / Congreve, M.S. / Devine, L.A. / Tisi, D. / O'Reilly, M. / Seavers, L.C. / Davis, D.J. / Curry, J. / Anthony, R. / Padova, A. / Murray, C.W. / Carr, R.A. / Jhoti, H.
History
DepositionNov 5, 2004Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 3, 2005Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)41,8803
Polymers41,3431
Non-polymers5372
Water7,116395
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)45.775, 85.305, 126.639
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 P38ALPHA / MAP KINASE P38ALPHA / CYTOKINE SUPPRESSIVE ANTI- ...MITOGEN-ACTIVATED PROTEIN KINASE P38ALPHA / MAP KINASE P38ALPHA / 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 / Fragment: KINASE DOMAIN, RESIDUES 1-360
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q16539, EC: 2.7.1.37
#2: Chemical ChemComp-LI2 / 3-FLUORO-5-MORPHOLIN-4-YL-N-[3-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-5-YL]BENZAMIDE


Mass: 444.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25FN4O2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 395 / Source method: isolated from a natural source / Formula: H2O
Compound detailsFUNCTION: RESPONDS TO ACTIVATION BY ENVIRONMENTAL STRESS, PRO- INFLAMMATORY CYTOKINES AND ...FUNCTION: RESPONDS TO ACTIVATION BY ENVIRONMENTAL STRESS, PRO- INFLAMMATORY CYTOKINES AND LIPOPOLYSACCHARIDE (LPS) BY PHOSPHORYLATING A NUMBER OF TRANSCRIPTION FACTORS, SUCH AS ELK1 AND ATF2 AND SEVERAL DOWNSTREAM KINASES, SUCH AS MAPKAPK2 AND MAPKAPK5. PLAYS A CRITICAL ROLE IN THE PRODUCTION OF SOME CYTOKINES, FOR EXAMPLE IL-6.
Sequence detailsTHE INITIAL MET WAS NOT OBSERVED IN THE SEQUENCING EXPERIMENT THAT DETERMINED THE SEQUENCE OF THE ...THE INITIAL MET WAS NOT OBSERVED IN THE SEQUENCING EXPERIMENT THAT DETERMINED THE SEQUENCE OF THE UNIPROT ENTRY, BUT THIS INITIAL MET IS PRESUMED TO EXIST AND IS DESCRIBED IN AN ANNOTATION IN THE UNIPROT ENTRY.

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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: 3.04 Å3/Da / Density % sol: 59.2 %
Crystal growpH: 7 / Details: pH 7.00

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 1.8→70.71 Å / Num. obs: 46857 / % possible obs: 90.8 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Biso Wilson estimate: 26.8 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 4.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0003refinement
MOSFLMdata reduction
SCALAdata scaling
DENCORphasing
RefinementMethod to determine structure: OTHER / Resolution: 1.8→70.71 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.921 / SU B: 2.884 / SU ML: 0.09 / Cross valid method: THROUGHOUT / ESU R: 0.151 / ESU R Free: 0.145 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED REGIONS AT A35, A172-174, A353-354
RfactorNum. reflection% reflectionSelection details
Rfree0.234 1829 5.1 %RANDOM
Rwork0.191 ---
obs0.194 34025 76.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.63 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å20 Å2
2---0.66 Å20 Å2
3---0.48 Å2
Refinement stepCycle: LAST / Resolution: 1.8→70.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2834 0 39 395 3268
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222942
X-RAY DIFFRACTIONr_bond_other_d0.0010.022676
X-RAY DIFFRACTIONr_angle_refined_deg1.5971.9783995
X-RAY DIFFRACTIONr_angle_other_deg0.77936220
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.285350
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.76723.986138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.46615505
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.8161519
X-RAY DIFFRACTIONr_chiral_restr0.0690.2442
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023229
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02596
X-RAY DIFFRACTIONr_nbd_refined0.20.2605
X-RAY DIFFRACTIONr_nbd_other0.1690.22719
X-RAY DIFFRACTIONr_nbtor_refined0.1740.21445
X-RAY DIFFRACTIONr_nbtor_other0.0820.21665
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.2313
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1480.212
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2170.242
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1840.218
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.01314.872310
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.33715.0392851
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.88716.7761398
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.83817.7631144
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.353 75
Rwork0.275 1095

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