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

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Basic information

Entry
Database: PDB / ID: 1wbt
TitleIdentification of novel p38 alpha MAP Kinase inhibitors using fragment-based lead generation.
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 14
KeywordsTRANSFERASE / ATP-BINDING / NUCLEAR PROTEIN / PHOSPHORYLATION / SERINE/THREONINE-PROTEIN KINASE / P38 MAP KINASE / INHIBITOR STRUCTURE
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-WBT / 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 1.3Jan 31, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name
Revision 1.4May 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)41,7882
Polymers41,3431
Non-polymers4451
Water4,576254
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)45.519, 85.602, 126.577
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 / P38 ALPHA MAP KINASE / MITOGEN-ACTIVATED PROTEIN KINASE P38 ALPHA / MAP KINASE P38ALPHA / CYTOKINE ...P38 ALPHA MAP KINASE / MITOGEN-ACTIVATED PROTEIN KINASE P38 ALPHA / 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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI BL21(DE3) (bacteria) / References: UniProt: Q16539, EC: 2.7.1.37
#2: Chemical ChemComp-WBT / 3-FLUORO-5-MORPHOLIN-4-YL-N-[1-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-6-YL]BENZAMIDE


Mass: 444.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25FN4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 254 / Source method: isolated from a natural source / Formula: H2O
Compound detailsCATALYTIC ACTIVITY: ATP + A PROTEIN = ADP + A PHOSPHOPROTEIN.

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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: 2→70.71 Å / Num. obs: 33834 / % possible obs: 94.4 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Biso Wilson estimate: 32.3 Å2 / Rmerge(I) obs: 0.11 / Net I/σ(I): 4.1

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Processing

Software
NameVersionClassification
REFMAC5.2.0003refinement
MOSFLMdata reduction
SCALAdata scaling
DENCORphasing
RefinementMethod to determine structure: OTHER / Resolution: 2→70.71 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.892 / SU B: 5.563 / SU ML: 0.155 / Cross valid method: THROUGHOUT / ESU R: 0.19 / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.276 1662 5.1 %RANDOM
Rwork0.227 ---
obs0.229 33834 97.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.18 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å20 Å20 Å2
2--1.14 Å20 Å2
3----1.09 Å2
Refinement stepCycle: LAST / Resolution: 2→70.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2834 0 33 254 3121
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222937
X-RAY DIFFRACTIONr_bond_other_d0.0010.022670
X-RAY DIFFRACTIONr_angle_refined_deg1.4791.9773990
X-RAY DIFFRACTIONr_angle_other_deg0.85736206
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0035350
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.21923.986138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.38115505
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9191519
X-RAY DIFFRACTIONr_chiral_restr0.0830.2442
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023229
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02596
X-RAY DIFFRACTIONr_nbd_refined0.20.2612
X-RAY DIFFRACTIONr_nbd_other0.1770.22728
X-RAY DIFFRACTIONr_nbtor_refined0.1780.21411
X-RAY DIFFRACTIONr_nbtor_other0.0850.21688
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1880.2174
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.120.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1970.236
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1430.25
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.55923.1632302
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.21523.4362851
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.12426.8371393
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.71928.4791139
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
Rfree0.362 100
Rwork0.276 1840

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