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- PDB-4aa4: P38ALPHA MAP KINASE BOUND TO CMPD 22 -

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Basic information

Entry
Database: PDB / ID: 4aa4
TitleP38ALPHA MAP KINASE BOUND TO CMPD 22
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 14
KeywordsTRANSFERASE / SERINE/THREONINE 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 / 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-QC0 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsGerhardt, S. / Hargreaves, D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: The Discovery of N-Cyclopropyl-4-Methyl-3-[6--(4-Methylpiperazin-1-Yl-4-Oxoquinazolin-3(4H)-Yl]Benzamide (Azd6703), a Clinical P38Alpha Map Kinase Inhibitor for the Treatment of Inflammatory Diseases
Authors: Brown, D.S. / Cumming, J.G. / Bethel, P. / Finlayson, J. / Gerhardt, S. / Nash, I. / Pauptit, R. / Pike, K.G. / Reid, A. / Snelson, W. / Swallow, S. / Thompson, C.
History
DepositionNov 30, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 6, 2012Group: Other
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3Oct 24, 2018Group: Data collection / Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_strain
Revision 1.4Jan 30, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.5Feb 6, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.6Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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 / _pdbx_database_status.status_code_sf / _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

Downloads & links

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Assembly

Deposited unit
A: MITOGEN-ACTIVATED PROTEIN KINASE 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4842
Polymers42,0411
Non-polymers4431
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.417, 75.042, 78.350
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 / CYTOKINE SUPPRESSIVE ANTI-INFLAMMATORY DRUG-BINDING PROTEIN / CSAID- ...MAP KINASE 14 / MAPK 14 / CYTOKINE SUPPRESSIVE ANTI-INFLAMMATORY DRUG-BINDING PROTEIN / CSAID-BINDING PROTEIN / CSBP / MAP KINASE MXI2 / MAX-INTERACTING PROTEIN 2 / MITOGEN-ACTIVATED PROTEIN KINASE P38 ALPHA / MAP KINASE P38 ALPHA / STRESS-ACTIVATED PROTEIN KINASE 2A / SAPK2A / P38ALPHA MAP KINASE


Mass: 42040.879 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PT7 3.3 / Production host: ESCHERICHIA COLI BL21(DE3) (bacteria)
References: UniProt: Q16539, mitogen-activated protein kinase, EC: 2.7.1.37
#2: Chemical ChemComp-QC0 / N-[4-METHYL-3-[6-(4-METHYLPIPERAZIN-1-YL)-4-OXIDANYLIDENE-QUINAZOLIN-3-YL]PHENYL]FURAN-3-CARBOXAMIDE


Mass: 443.498 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25N5O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE INHIBITOR N-[4-METHYL-3-[6-(4-METHYLPIPERAZIN-1-YL)-4- OXIDANYLIDENE-QUINAZOLIN-3-YL]PHENYL] ...THE INHIBITOR N-[4-METHYL-3-[6-(4-METHYLPIPERAZIN-1-YL)-4- OXIDANYLIDENE-QUINAZOLIN-3-YL]PHENYL]FURAN-3- CARBOXAMIDE IS REPRESENTED BY RESIDUE QC0. THE FURAN RING IS NOT A DELOCALIZED ELECTRON SYSTEM BUT HAS DOUBLE BONDS BETWEEN C21 - C25 AND C22 - C23.
Sequence detailsNTERMIMAL HEXA-HIS EXPRESSION TAG.

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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: 2.34 Å3/Da / Density % sol: 47.51 % / Description: NONE
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 6-10% PEG-MME 5000, PH 6.5, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Feb 4, 2003 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→21.42 Å / Num. obs: 17683 / % possible obs: 92.1 % / Observed criterion σ(I): 0 / Redundancy: 3 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 14.3
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.29 / Mean I/σ(I) obs: 3.7 / % possible all: 84.4

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Processing

Software
NameVersionClassification
REFMAC5.6.0113refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2BAL

2bal


Resolution: 2.3→21.42 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.928 / SU B: 17.727 / SU ML: 0.214 / Cross valid method: THROUGHOUT / ESU R: 0.468 / ESU R Free: 0.272 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED REGIONS WERE NOT INCLUDED IN THE MODEL.
RfactorNum. reflection% reflectionSelection details
Rfree0.25501 804 5.1 %RANDOM
Rwork0.21122 ---
obs0.21353 14904 88.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.288 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å20 Å20 Å2
2---2.18 Å20 Å2
3---2.29 Å2
Refinement stepCycle: LAST / Resolution: 2.3→21.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2800 0 33 28 2861
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.022902
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6831.9773945
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8165345
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.14423.942137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.45915494
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.4891519
X-RAY DIFFRACTIONr_chiral_restr0.1120.2438
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212201
X-RAY DIFFRACTIONr_gen_planes_other
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 60 -
Rwork0.276 792 -
obs--69.72 %
Refinement TLS params.Method: refined / Origin x: 6.269 Å / Origin y: 4.322 Å / Origin z: 15.42 Å
111213212223313233
T0.2458 Å20.0032 Å20.0278 Å2-0.0528 Å20.0094 Å2--0.0089 Å2
L4.2954 °2-0.3946 °20.5715 °2-1.9253 °2-0.3198 °2--1.4746 °2
S0.0353 Å °-0.2173 Å °0.0602 Å °0.0581 Å °-0.0726 Å °-0.0009 Å °-0.0586 Å °-0.0345 Å °0.0373 Å °

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