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- PDB-1w82: p38 Kinase crystal structure in complex with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 1w82
Titlep38 Kinase crystal structure in complex with small molecule inhibitor
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 14
KeywordsKINASE/INHIBITOR / KINASE-INHIBITOR COMPLEX / P38 / KINASE / 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-L10 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.2 Å
AuthorsTickle, J. / Jhoti, H. / Cleasby, A. / Devine, L.
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. / Carr, M. / Woodhead, A. / Walker, M. / Congreve, M. / Devine, L. / Tisi, D. / O'Reilly, M. / Seavers, L. / Davis, D. / Curry, J. / ...Authors: Gill, A. / Frederickson, M. / Cleasby, A. / Woodhead, S. / Carr, M. / Woodhead, A. / Walker, M. / Congreve, M. / Devine, L. / Tisi, D. / O'Reilly, M. / Seavers, L. / Davis, D. / Curry, J. / Anthony, R. / Padova, A. / Murray, C. / Carr, R. / Jhoti, H.
History
DepositionSep 16, 2004Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 8, 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:
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Assembly

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


Theoretical massNumber of molelcules
Total (without water)41,7122
Polymers41,3431
Non-polymers3691
Water9,512528
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)45.684, 85.369, 126.000
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 MAP KINASE


Mass: 41343.195 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: KINASE DOMAIN / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI BL21(DE3) (bacteria) / References: UniProt: Q16539, EC: 2.7.1.37
#2: Chemical ChemComp-L10 / N-[(3Z)-5-TERT-BUTYL-2-PHENYL-1,2-DIHYDRO-3H-PYRAZOL-3-YLIDENE]-N'-(4-CHLOROPHENYL)UREA


Mass: 368.860 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21ClN4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 528 / 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: 2.97 Å3/Da / Density % sol: 58.61 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.933
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 25791 / % possible obs: 92.6 % / Observed criterion σ(I): 2 / Redundancy: 2.2 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 5.6

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Processing

SoftwareName: REFMAC / Version: 5.2.0003A / Classification: refinement
RefinementMethod to determine structure: OTHER / Resolution: 2.2→70.71 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.906 / SU B: 5.177 / SU ML: 0.132 / Cross valid method: THROUGHOUT / ESU R: 0.242 / ESU R Free: 0.21 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.235 1229 5.2 %RANDOM
Rwork0.171 ---
obs0.174 22487 92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.48 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å20 Å20 Å2
2--0.22 Å20 Å2
3----0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.2→70.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2834 0 26 528 3388
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222928
X-RAY DIFFRACTIONr_bond_other_d0.0030.022666
X-RAY DIFFRACTIONr_angle_refined_deg1.4791.9743979
X-RAY DIFFRACTIONr_angle_other_deg1.16136192
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1145350
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.3723.986138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.4915505
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.5411519
X-RAY DIFFRACTIONr_chiral_restr0.0810.2442
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023228
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02595
X-RAY DIFFRACTIONr_nbd_refined0.1730.3512
X-RAY DIFFRACTIONr_nbd_other0.1210.32673
X-RAY DIFFRACTIONr_nbtor_refined0.1620.51397
X-RAY DIFFRACTIONr_nbtor_other0.0810.51651
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1060.5185
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0180.51
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0470.36
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1010.350
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1480.513
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.96311.7722304
X-RAY DIFFRACTIONr_mcbond_other0.30511.527702
X-RAY DIFFRACTIONr_mcangle_it2.07611.7972851
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.76913.0461370
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.75813.6031128
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→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.269 78 -
Rwork0.215 1486 -
obs--84.13 %

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