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- PDB-3e93: Crystal Structure of P38 Kinase in Complex with A Biaryl Amide In... -

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Basic information

Entry
Database: PDB / ID: 3.0E+93
TitleCrystal Structure of P38 Kinase in Complex with A Biaryl Amide Inhibitor
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE / P38 / SERINE/THREONINE PROTEIN KINASE / MAP KINASE / ATP-binding / Kinase / Nucleotide-binding / Nucleus / Phosphoprotein / Serine/threonine-protein kinase
Function / homology
Function and homology information


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 / DSCAM interactions / cartilage condensation ...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 / DSCAM interactions / cartilage condensation / cellular response to UV-B / Platelet sensitization by LDL / stress-activated protein kinase signaling cascade / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / positive regulation of muscle cell differentiation / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / glucose import / response to dietary excess / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / MAP kinase kinase activity / response to muramyl dipeptide / RHO GTPases Activate NADPH Oxidases / regulation of ossification / MAP kinase activity / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / signal transduction in response to DNA damage / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / 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 / positive regulation of erythrocyte differentiation / placenta development / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / negative regulation of canonical Wnt signaling pathway / response to insulin / NOD1/2 Signaling Pathway / bone development / cell morphogenesis / platelet activation / osteoblast differentiation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / cellular senescence / cellular response to tumor necrosis factor / protein phosphatase binding / peptidyl-serine phosphorylation / angiogenesis / Oxidative Stress Induced Senescence / secretory granule lumen / cellular response to lipopolysaccharide / 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 / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / 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 / Serine/Threonine protein kinases, catalytic 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-19B / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsSomers, D.O. / Patel, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Kinase array design, back to front: Biaryl amides
Authors: Baldwin, I. / Bamborough, P. / Haslam, C.G. / Hunjan, S.S. / Longstaff, T. / Mooney, C.J. / Patel, S. / Quinn, J. / Somers, D.O.
History
DepositionAug 21, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Sep 30, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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)43,4405
Polymers42,6671
Non-polymers7734
Water7,945441
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.768, 86.044, 126.285
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAPK14 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti- ...Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-binding protein / CSBP / MAX-interacting protein 2 / MAP kinase MXI2 / SAPK2A


Mass: 42666.738 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pRSETA / Production host: Escherichia coli (E. coli) / Strain (production host): BRL
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-19B / 4-methyl-N-(3-morpholin-4-ylphenyl)-3-(3-piperidin-4-yl-1,2-benzisoxazol-6-yl)benzamide


Mass: 496.600 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H32N4O3
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 441 / 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: 2.91 Å3/Da / Density % sol: 57.79 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 18-22% PEG 5000MME, 0.18M ammonium sulphate, 3-4% jeffamine, 0.1M ADA, pH 6.5, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Nov 16, 2001 / Details: MIRRORS
RadiationMonochromator: Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→35 Å / Num. obs: 31814 / % possible obs: 91.8 % / Biso Wilson estimate: 28 Å2 / Rmerge(I) obs: 0.076 / Χ2: 1.001 / Net I/σ(I): 14.1
Reflection shellResolution: 2→2.07 Å / Rmerge(I) obs: 0.506 / Mean I/σ(I) obs: 2.1 / Num. unique all: 3042 / Rsym value: 0.506 / Χ2: 1.001 / % possible all: 89.2

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.006data extraction
REFMAC5phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1WFC

1wfc


Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.934 / WRfactor Rfree: 0.23 / WRfactor Rwork: 0.17 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.86 / SU B: 6.556 / SU ML: 0.101 / SU R Cruickshank DPI: 0.152 / SU Rfree: 0.154 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: ISOTROPIC / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.152 / ESU R Free: 0.154 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.228 1598 5 %RANDOM
Rwork0.169 ---
obs0.171 31676 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 69.59 Å2 / Biso mean: 37.073 Å2 / Biso min: 17.17 Å2
Baniso -1Baniso -2Baniso -3
1--0.71 Å20 Å20 Å2
2--0.32 Å20 Å2
3---0.39 Å2
Refinement stepCycle: LAST / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2800 0 55 441 3296
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222933
X-RAY DIFFRACTIONr_angle_refined_deg1.2441.9833982
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.7855.057351
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.26824.161137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.54615501
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.841518
X-RAY DIFFRACTIONr_chiral_restr0.0880.2441
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022209
X-RAY DIFFRACTIONr_nbd_refined0.2030.21372
X-RAY DIFFRACTIONr_nbtor_refined0.3040.22010
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1550.2360
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.180.230
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1070.228
X-RAY DIFFRACTIONr_mcbond_it1.10321803
X-RAY DIFFRACTIONr_mcangle_it1.77132827
X-RAY DIFFRACTIONr_scbond_it2.7494.51313
X-RAY DIFFRACTIONr_scangle_it3.89761153
LS refinement shellResolution: 2→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.382 108 -
Rwork0.271 2065 -
all-2173 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.33941.249-0.18112.8972-1.23323.8365-0.21460.1422-0.0659-0.4370.0798-0.18650.165-0.09890.1347-0.17490.01150.0135-0.13820.0204-0.121232.101730.764329.6217
22.2589-1.25440.04861.8430.30981.40930.010.1388-0.0544-0.0850.0040.03130.0277-0.0019-0.0139-0.1982-0.0220.0032-0.1677-0.0093-0.234552.73923.225849.8658
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 109
2X-RAY DIFFRACTION1A318 - 353
3X-RAY DIFFRACTION2A110 - 317

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