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

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Basic information

Entry
Database: PDB / ID: 1wbv
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 / 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 / NFAT protein binding / positive regulation of myotube differentiation / 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 / response to dietary excess / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / Regulation of MITF-M-dependent genes involved in pigmentation / MAP kinase kinase activity / signal transduction in response to DNA damage / regulation of ossification / MAP kinase activity / cellular response to vascular endothelial growth factor stimulus / RHO GTPases Activate NADPH Oxidases / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / vascular endothelial growth factor receptor signaling pathway / 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 / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / positive regulation of D-glucose import / 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 / cell morphogenesis / positive regulation of reactive oxygen species metabolic process / chemotaxis / spindle pole / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / cellular senescence / 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-LI3 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2 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)42,0376
Polymers41,3431
Non-polymers6945
Water10,251569
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)45.504, 86.860, 125.205
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-LI3 / 3-FLUORO-N-1H-INDOL-5-YL-5-MORPHOLIN-4-YLBENZAMIDE


Mass: 339.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18FN3O2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 569 / 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.

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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: 3.03 Å3/Da / Density % sol: 59.11 %
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: 2→70.71 Å / Num. obs: 34365 / % possible obs: 93.7 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Biso Wilson estimate: 28.3 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 7.1

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Processing

Software
NameVersionClassification
REFMAC5.2.0003Arefinement
MOSFLMdata reduction
SCALAdata scaling
DENCORphasing
RefinementMethod to determine structure: OTHER / Resolution: 2→70.71 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.923 / SU B: 3.562 / SU ML: 0.103 / Cross valid method: THROUGHOUT / ESU R: 0.169 / ESU R Free: 0.165 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.DISORDERED REGIONS AT A35, A170-A175
RfactorNum. reflection% reflectionSelection details
Rfree0.233 1610 5.1 %RANDOM
Rwork0.177 ---
obs0.18 30241 92.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.69 Å2
Baniso -1Baniso -2Baniso -3
1-0.37 Å20 Å20 Å2
2---1.28 Å20 Å2
3---0.91 Å2
Refinement stepCycle: LAST / Resolution: 2→70.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2834 0 47 569 3450
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222946
X-RAY DIFFRACTIONr_bond_other_d0.0010.022687
X-RAY DIFFRACTIONr_angle_refined_deg1.2531.9793996
X-RAY DIFFRACTIONr_angle_other_deg0.79536244
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1545350
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.47423.986138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.26215505
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2791519
X-RAY DIFFRACTIONr_chiral_restr0.0790.2442
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023221
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02593
X-RAY DIFFRACTIONr_nbd_refined0.2050.2611
X-RAY DIFFRACTIONr_nbd_other0.1710.22731
X-RAY DIFFRACTIONr_nbtor_refined0.1750.21423
X-RAY DIFFRACTIONr_nbtor_other0.0820.21677
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1660.2476
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.110.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1990.272
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1440.233
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.16619.1932309
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.56419.1582851
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.16723.3891392
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.14225.0971145
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→2.05 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.253 93
Rwork0.208 1848

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