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- PDB-3mw1: p38 kinase Crystal structure in complex with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 3mw1
Titlep38 kinase Crystal structure in complex with small molecule inhibitor
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE inhibitor / p38 MAP KINASE / TRANSFERASE / INHIBITOR COMPLEX / 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 / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion ...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 / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / 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 / fatty acid oxidation / response to dietary excess / cellular response to lipoteichoic acid / response to muramyl dipeptide / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / signal transduction in response to DNA damage / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / RHO GTPases Activate NADPH Oxidases / mitogen-activated protein kinase / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / negative regulation of hippo signaling / positive regulation of myoblast differentiation / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / p38MAPK events / positive regulation of brown fat cell differentiation / response to muscle stretch / striated muscle cell differentiation / positive regulation of interleukin-12 production / positive regulation of erythrocyte differentiation / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / positive regulation of D-glucose import / cellular response to ionizing radiation / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / response to insulin / 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 / cell morphogenesis / chemotaxis / spindle pole / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / secretory granule lumen / protein phosphatase binding / 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 / 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 / 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. / : / 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
Chem-MIH / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSegarra, V. / Caturla, F. / Lumeras, W. / Roca, R. / Fisher, M. / Lamers, M.
Citation
Journal: J.Med.Chem. / Year: 2011
Title: 1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase
Authors: Lumeras, W. / Vidal, L. / Vidal, B. / Balague, C. / Orellana, A. / Maldonado, M. / Dominguez, M. / Segarra, V. / Caturla, F.
#1: Journal: J.Med.Chem. / Year: 2009
Title: Design, synthesis, and structure-activity relationships of aminopyridine N-oxides, a novel scaffold for the potent and selective inhibition of p38 mitogen activated protein kinase
Authors: Lumeras, W. / Caturla, J.-F. / Vidal, L. / Esteve, C. / Balague, C. / Orellana, A. / Dominguez, M. / Roca, R. / Huerta, J.M. / Godessart, N. / Vidal, B.
History
DepositionMay 5, 2010Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Apr 27, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 7, 2011Group: Database references
Revision 1.3Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)41,6982
Polymers41,2121
Non-polymers4861
Water64936
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.260, 87.230, 122.810
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 / MAP kinase 14 / MAPK 14 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / ...MAP kinase 14 / MAPK 14 / 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: 41212.000 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK14 / Plasmid: Sareum proprietary pT7-NH2 vector / Production host: Escherichia coli (E. coli) / Strain (production host): DH10B-R
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-MIH / 8-(2,6-dichlorophenyl)-4-(2,4-difluorophenyl)-2-piperidin-4-yl-1,7-naphthyridine 7-oxide


Mass: 486.341 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19Cl2F2N3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 36 / 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: 2.94 Å3/Da / Density % sol: 58.2 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 22% PEG 3350, 0.2M NaCl, 0.1 M Bis-Tris pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.8→20 Å / Num. obs: 11267 / % possible obs: 90.1 % / Rmerge(I) obs: 0.11
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 2.92 % / Rmerge(I) obs: 0.377 / % possible all: 98.4

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Processing

Software
NameVersionClassificationNB
REFMAC5.5.0072refinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3HRB

3hrb


Resolution: 2.8→19.93 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.87 / Occupancy max: 1 / Occupancy min: 1 / SU B: 19.847 / SU ML: 0.379 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.51 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.33907 547 4.9 %RANDOM
Rwork0.25516 10720 --
obs0.25902 11267 90.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 69.25 Å2 / Biso mean: 40.425 Å2 / Biso min: 21.97 Å2
Baniso -1Baniso -2Baniso -3
1--0.41 Å20 Å20 Å2
2--0.27 Å20 Å2
3---0.13 Å2
Refinement stepCycle: LAST / Resolution: 2.8→19.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2725 0 33 36 2794
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222824
X-RAY DIFFRACTIONr_bond_other_d0.0010.021871
X-RAY DIFFRACTIONr_angle_refined_deg1.1991.9773843
X-RAY DIFFRACTIONr_angle_other_deg0.85534570
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2285339
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.15324.341129
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.70615472
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4851515
X-RAY DIFFRACTIONr_chiral_restr0.0620.2432
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213103
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02560
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4551.51710
X-RAY DIFFRACTIONr_mcbond_other0.0531.5679
X-RAY DIFFRACTIONr_mcangle_it0.85722766
X-RAY DIFFRACTIONr_scbond_it0.92731114
X-RAY DIFFRACTIONr_scangle_it1.6234.51077
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.871 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.496 52 -
Rwork0.349 817 -
all-869 -
obs--98.41 %

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