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- PDB-8yd9: Crystal structure of p38alpha with an allosteric inhibitor 3 -

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Basic information

Entry
Database: PDB / ID: 8yd9
TitleCrystal structure of p38alpha with an allosteric inhibitor 3
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / STRUCTURAL GENOMICS / TRANSFERASE-TRANSFERASE 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 / 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 / mitogen-activated protein kinase p38 binding / Platelet sensitization by LDL / positive regulation of muscle cell differentiation / Myogenesis / NFAT protein binding / positive regulation of myotube differentiation / 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 / MAP kinase kinase activity / fatty acid oxidation / 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 / mitogen-activated protein kinase / JUN kinase activity / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte 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 / bone development / cell morphogenesis / platelet activation / cellular response to virus / spindle pole / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / cellular senescence / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / peptidyl-serine phosphorylation / 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 / apoptotic process / positive regulation of gene expression / Neutrophil degranulation / 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. / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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
Similarity search - Domain/homology
Chem-6GI / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsHasegawa, S. / Kinoshita, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: To Be Published
Title: Identification of a novel target site for ATP-independent p38 alpha inhibitors
Authors: Kinoshita, T. / Hasegawa, S.
#1: Journal: Biochem Biophys Res Commun / Year: 2022
Title: Identification of a novel target site for ATP-independent ERK2 inhibitors.
Authors: Yoshida, M. / Nagao, H.
History
DepositionFeb 19, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release

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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)42,2857
Polymers41,3431
Non-polymers9426
Water7,224401
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.785, 85.643, 126.935
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAP kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID- ...MAP kinase 14 / MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-binding protein / CSBP / MAP kinase MXI2 / MAX-interacting protein 2 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Stress-activated protein kinase 2a / SAPK2a


Mass: 41343.195 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2, SAPK2A / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-6GI / 13-[4-({Imidazo[1,2-a]pyridin-2-yl}methoxy)phenyl]-4,8-dioxa-12,14,16,18-tetraazatetracyclo[9.7.0.0^{3,9}.0^{12,17}]octadeca-1(11),2,9,15,17-pentaen-15-amine


Mass: 481.506 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H23N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 401 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.01 Å3/Da / Density % sol: 59.13 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: anmonium acetate, HEPES, PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 29, 2022
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 1.66→45.61 Å / Num. obs: 59663 / % possible obs: 99 % / Redundancy: 5 % / Biso Wilson estimate: 31.85 Å2 / CC1/2: 0.996 / Net I/σ(I): 8.34
Reflection shellResolution: 1.66→1.76 Å / Num. unique obs: 59663 / CC1/2: 0.996

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.66→45.61 Å / SU ML: 0.2291 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.8297
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2049 3074 5 %
Rwork0.1604 58428 -
obs0.1627 59663 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.42 Å2
Refinement stepCycle: LAST / Resolution: 1.66→45.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2825 0 66 401 3292
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00773173
X-RAY DIFFRACTIONf_angle_d0.95824332
X-RAY DIFFRACTIONf_chiral_restr0.0572476
X-RAY DIFFRACTIONf_plane_restr0.0093558
X-RAY DIFFRACTIONf_dihedral_angle_d7.2613438
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.66-1.670.37031340.30442549X-RAY DIFFRACTION97.67
1.67-1.70.31391390.25662630X-RAY DIFFRACTION100
1.7-1.730.30111360.23172589X-RAY DIFFRACTION100
1.73-1.760.28161400.23632666X-RAY DIFFRACTION100
1.76-1.790.33431380.25032607X-RAY DIFFRACTION100
1.79-1.830.32591380.25732633X-RAY DIFFRACTION100
1.83-1.870.31861390.24132630X-RAY DIFFRACTION100
1.87-1.910.28541390.20782638X-RAY DIFFRACTION100
1.91-1.960.21891370.16672607X-RAY DIFFRACTION100
1.96-2.010.20111390.16652645X-RAY DIFFRACTION99.96
2.01-2.070.23121390.16022646X-RAY DIFFRACTION99.96
2.07-2.140.19211380.16372628X-RAY DIFFRACTION100
2.14-2.210.20931410.16512660X-RAY DIFFRACTION99.93
2.21-2.30.21871380.16572659X-RAY DIFFRACTION100
2.3-2.410.2531400.1562650X-RAY DIFFRACTION100
2.41-2.530.191400.15842670X-RAY DIFFRACTION99.82
2.53-2.690.19731420.15682684X-RAY DIFFRACTION99.96
2.69-2.90.19371390.1692642X-RAY DIFFRACTION99.86
2.9-3.190.22741420.16732696X-RAY DIFFRACTION99.93
3.19-3.650.18791410.14142687X-RAY DIFFRACTION99.44
3.65-4.60.17371450.12552745X-RAY DIFFRACTION99.55
4.61-37.130.18281500.16292867X-RAY DIFFRACTION99.8

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