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- PDB-1ove: The structure of p38 alpha in complex with a dihydroquinolinone -

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Basic information

Entry
Database: PDB / ID: 1ove
TitleThe structure of p38 alpha in complex with a dihydroquinolinone
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / MAp kinase / hydrophobic pocket / kinase domain / linker region
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 / 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 / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / 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 / cellular response to lipoteichoic acid / response to dietary excess / 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 / osteoclast differentiation / positive regulation of erythrocyte differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / positive regulation of D-glucose import across plasma membrane / 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-358 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsFitzgerald, C.E. / Patel, S.B. / Becker, J.W. / Cameron, P.M. / Zaller, D. / Pikounis, V.B. / O'Keefe, S.J. / Scapin, G.
Citation
Journal: Nat.Struct.Biol. / Year: 2003
Title: Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity
Authors: Fitzgerald, C.E. / Patel, S.B. / Becker, J.W. / Cameron, P.M. / Zaller, D. / Pikounis, V.B. / O'Keefe, S.J. / Scapin, G.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2003
Title: Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase
Authors: Stelmach, J.E. / Liu, L. / Patel, S.B. / Pivnichny, J.V. / Scapin, G. / Singh, S. / Hop, C.E. / Wang, Z. / Cameron, P.M. / Nichols, E.A. / O'Keefe, S.J. / O'Neill, E.A. / Schmatz, D.M. / ...Authors: Stelmach, J.E. / Liu, L. / Patel, S.B. / Pivnichny, J.V. / Scapin, G. / Singh, S. / Hop, C.E. / Wang, Z. / Cameron, P.M. / Nichols, E.A. / O'Keefe, S.J. / O'Neill, E.A. / Schmatz, D.M. / Schwartz, C.D. / Thompson, C.M. / Zaller, D.M. / Doherty, J.B.
History
DepositionMar 26, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 27, 2021Group: Database references / Derived calculations / Category: database_2 / 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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Aug 16, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)42,5623
Polymers41,9831
Non-polymers5792
Water5,188288
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.009, 87.100, 122.613
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 p38 / MAP kinase p38 / Cytokine suppressive anti-inflammatory drug ...Mitogen-activated protein kinase p38 / MAP kinase p38 / Cytokine suppressive anti-inflammatory drug binding protein / CSAID binding protein / CSBP / MAX-interacting protein 2 / MAP kinase MXI2


Mass: 41982.871 Da / Num. of mol.: 1 / Mutation: C162S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK14 / Plasmid: pET / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q16539, EC: 2.7.1.37
#2: Chemical ChemComp-358 / 1-(2,6-DICHLOROPHENYL)-5-(2,4-DIFLUOROPHENYL)-7-PIPERIDIN-4-YL-3,4-DIHYDROQUINOLIN-2(1H)-ONE


Mass: 487.368 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22Cl2F2N2O
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 288 / 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: 2.71 Å3/Da / Density % sol: 54.22 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: Sodium citrate, Ammonium sulfate, HEPES buffer, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K
Crystal grow
*PLUS
pH: 7.5 / Method: vapor diffusion / Details: Wilson, K.P., (1996) J.Biol.Chem., 271, 27696.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formula
124 mg/mlprotein1drop
230 mMHEPES1drop
36 mMDTT1drop
40.06 M1dropNaCl
53 %glycerol1drop
616 mMNa HEPES1drop
70.224 Msodium citrate1drop
852 mMammonium sulfate1drop
940 mMNa HEPES1reservoir
100.56 Msodium citrate1reservoir
11130 mMammonium sulfate1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 15, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→35 Å / Num. all: 29093 / Num. obs: 29079 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7.1 % / Biso Wilson estimate: 25.3 Å2 / Rsym value: 0.094 / Net I/σ(I): 6.2
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 6.6 % / Mean I/σ(I) obs: 1.7 / Num. unique all: 2867 / Rsym value: 0.399 / % possible all: 100
Reflection
*PLUS
% possible obs: 100 % / Rmerge(I) obs: 0.094
Reflection shell
*PLUS
% possible obs: 100 % / Num. unique obs: 2867 / Rmerge(I) obs: 0.399

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Processing

Software
NameClassification
HKL-2000data collection
SCALEPACKdata scaling
CNSrefinement
HKL-2000data reduction
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1OUK

1ouk


Resolution: 2.1→25 Å / Isotropic thermal model: Anisotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: As implemented in CNX
RfactorNum. reflection% reflectionSelection details
Rfree0.233 1426 5 %Random; 5% data flagged
Rwork0.192 ---
obs0.195 28922 100 %-
all-28930 --
Solvent computationSolvent model: MASK / Bsol: 0.39 Å2 / ksol: 48.66 e/Å3
Displacement parametersBiso mean: 29 Å2
Baniso -1Baniso -2Baniso -3
1-7.485 Å22.979 Å2-10.464 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.23 Å0.16 Å
Refinement stepCycle: LAST / Resolution: 2.1→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2807 0 39 288 3134
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.011
X-RAY DIFFRACTIONc_angle_deg1.42
X-RAY DIFFRACTIONc_dihedral_angle_d22.1
X-RAY DIFFRACTIONc_improper_angle_d0.89
LS refinement shellResolution: 2.1→2.18 Å
RfactorNum. reflection% reflection
Rfree0.302 122 5 %
Rwork0.228 2731 -
obs-2853 100 %
Refinement
*PLUS
Lowest resolution: 25 Å
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.1
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.89

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