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

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Basic information

Entry
Database: PDB / ID: 1wbw
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 / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / cellular response to UV-B / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / 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 / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / JUN kinase activity / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / positive regulation of myoblast differentiation / vascular endothelial growth factor receptor signaling pathway / skeletal muscle tissue development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / 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 / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / positive regulation of D-glucose import / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / response to insulin / placenta development / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / cell morphogenesis / bone development / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / spindle pole / chemotaxis / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / secretory granule lumen / Oxidative Stress Induced Senescence / angiogenesis / 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
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
3-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINE / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.41 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. / 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. / Davis, D.J. ...Authors: Gill, A. / 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. / Davis, D.J. / Curry, J. / Anthony, R. / Padova, A. / Murray, C.W. / Carr, R.A.E. / 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)41,5932
Polymers41,3431
Non-polymers2501
Water4,792266
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)45.291, 86.025, 126.587
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-LI4 / 3-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINE


Mass: 250.295 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H14N2O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 266 / 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: 3.05 Å3/Da / Density % sol: 59.38 %
Crystal growpH: 7 / Details: pH 7.00

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54178
DetectorType: MSC / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.41→29.11 Å / Num. obs: 18684 / % possible obs: 78.7 % / Observed criterion σ(I): 2 / Redundancy: 2 % / Biso Wilson estimate: 36.1 Å2 / Rmerge(I) obs: 0.13 / Net I/σ(I): 6.2

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Processing

Software
NameVersionClassification
REFMAC5.2.0003Arefinement
d*TREKdata reduction
d*TREKdata scaling
DENCORphasing
RefinementMethod to determine structure: OTHER / Resolution: 2.41→29.11 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.875 / SU B: 8.844 / SU ML: 0.207 / Cross valid method: THROUGHOUT / ESU R: 0.372 / ESU R Free: 0.281 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED REGIONS ARE AT A14-A15,A35, A170- A175,A353-A354
RfactorNum. reflection% reflectionSelection details
Rfree0.273 955 5.1 %RANDOM
Rwork0.197 ---
obs0.201 17729 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.2 Å2
Baniso -1Baniso -2Baniso -3
1--1.14 Å20 Å20 Å2
2--1.22 Å20 Å2
3----0.09 Å2
Refinement stepCycle: LAST / Resolution: 2.41→29.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2834 0 19 266 3119
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222921
X-RAY DIFFRACTIONr_bond_other_d0.0010.022645
X-RAY DIFFRACTIONr_angle_refined_deg1.4041.9713967
X-RAY DIFFRACTIONr_angle_other_deg0.83436150
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4395350
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.85723.986138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.54315505
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7351519
X-RAY DIFFRACTIONr_chiral_restr0.0780.2442
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023214
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02583
X-RAY DIFFRACTIONr_nbd_refined0.2060.2620
X-RAY DIFFRACTIONr_nbd_other0.1790.22714
X-RAY DIFFRACTIONr_nbtor_refined0.1770.21406
X-RAY DIFFRACTIONr_nbtor_other0.0870.21687
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1740.2198
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1060.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2470.220
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1390.213
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.58316.5892295
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.09916.6452851
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.45318.8441367
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.28219.6151116
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: 2.41→2.47 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.331 66
Rwork0.239 1026

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