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- PDB-8x3m: Crystal structure of p38alpha with an allosteric inhibitor 2 -

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Basic information

Entry
Database: PDB / ID: 8x3m
TitleCrystal structure of p38alpha with an allosteric inhibitor 2
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / protein kinase MAPK family allosteric inhibitor covalent bond
Function / homology
Function and homology information


positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / CD163 mediating an anti-inflammatory response / stress-activated protein kinase signaling cascade / 3'-UTR-mediated mRNA stabilization / cell surface receptor protein serine/threonine kinase signaling pathway / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / CD163 mediating an anti-inflammatory response / stress-activated protein kinase signaling cascade / 3'-UTR-mediated mRNA stabilization / cell surface receptor protein serine/threonine kinase signaling pathway / 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 / Myogenesis / Platelet sensitization by LDL / positive regulation of myotube differentiation / NFAT protein binding / Activation of the AP-1 family of transcription factors / regulation of cytokine production involved in inflammatory response / ERK/MAPK targets / p38MAPK cascade / cellular response to lipoteichoic acid / response to dietary excess / fatty acid oxidation / response to muramyl dipeptide / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / MAP kinase activity / cellular response to vascular endothelial growth factor stimulus / regulation of ossification / mitogen-activated protein kinase / RHO GTPases Activate NADPH Oxidases / vascular endothelial growth factor receptor signaling pathway / chondrocyte differentiation / 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 / positive regulation of brown fat cell differentiation / response to muscle stretch / p38MAPK events / signal transduction in response to DNA damage / 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 / stem cell differentiation / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / positive regulation of D-glucose import across plasma membrane / activated TAK1 mediates p38 MAPK activation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / platelet activation / response to insulin / cellular response to virus / bone development / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / cell morphogenesis / spindle pole / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / MAPK cascade / cellular response to lipopolysaccharide / secretory granule lumen / angiogenesis / protein phosphatase binding / Oxidative Stress Induced Senescence / transcription by RNA polymerase II / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / 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. / : / 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-B8Z / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsHasegawa, S. / Kinoshita, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Biochem.Biophys.Res.Commun. / Year: 2024
Title: Distinct binding modes of a benzothiazole derivative confer structural bases for increasing ERK2 or p38 alpha MAPK selectivity.
Authors: Hasegawa, S. / Yoshida, M. / Nagao, H. / Sugiyama, H. / Sawa, M. / Kinoshita, T.
History
DepositionNov 14, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 20, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 5, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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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)42,2002
Polymers41,7551
Non-polymers4451
Water8,611478
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.366, 85.500, 125.669
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: 41754.648 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-B8Z / ~{N}-(5,6-dimethoxy-1,3-benzothiazol-2-yl)-2-[(4-fluoranylphenoxy)methyl]-1,3-thiazole-4-carboxamide


Mass: 445.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H16FN3O4S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 478 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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: 2.95 Å3/Da / Density % sol: 58.35 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1M Ammonium acetate, 0.1M HEPES pH7.5, 15% w/v 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: Feb 7, 2022
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 1.85→42.75 Å / Num. obs: 39303 / % possible obs: 91.6 % / Redundancy: 5 % / Biso Wilson estimate: 41.81 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.067 / Net I/σ(I): 11.99
Reflection shellResolution: 1.85→1.96 Å / Redundancy: 5 % / Rmerge(I) obs: 0.067 / Num. unique obs: 39303 / CC1/2: 0.997 / % possible all: 91.6

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→42.75 Å / SU ML: 0.2785 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.4198
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2257 1962 5 %
Rwork0.1811 37298 -
obs0.1833 39260 91.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.05 Å2
Refinement stepCycle: LAST / Resolution: 1.85→42.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2825 0 30 478 3333
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01263220
X-RAY DIFFRACTIONf_angle_d1.04184405
X-RAY DIFFRACTIONf_chiral_restr0.0652485
X-RAY DIFFRACTIONf_plane_restr0.0091570
X-RAY DIFFRACTIONf_dihedral_angle_d8.3158443
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.890.42351270.38622392X-RAY DIFFRACTION82.62
1.89-1.940.37331300.31012497X-RAY DIFFRACTION88.3
1.94-20.28061300.28032457X-RAY DIFFRACTION86.03
2-2.070.31811310.24962499X-RAY DIFFRACTION86.26
2.07-2.140.28151330.24432523X-RAY DIFFRACTION88.74
2.14-2.230.27411330.22032524X-RAY DIFFRACTION88.04
2.23-2.330.26961380.20472627X-RAY DIFFRACTION90.8
2.33-2.450.25781380.19782626X-RAY DIFFRACTION91.34
2.45-2.60.24851430.22712X-RAY DIFFRACTION93.27
2.6-2.80.22611440.20092731X-RAY DIFFRACTION94.45
2.8-3.090.23951470.19632788X-RAY DIFFRACTION95.66
3.09-3.530.20361510.16992893X-RAY DIFFRACTION98.16
3.53-4.450.17621550.142956X-RAY DIFFRACTION99.42
4.45-42.750.23031620.16923073X-RAY DIFFRACTION98.69

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