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- PDB-6yjc: Crystal structure of p38alpha in complex with SR154 -

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Basic information

Entry
Database: PDB / ID: 6yjc
TitleCrystal structure of p38alpha in complex with SR154
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / Kinase / Inhibitor / MAPK14 / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / Regulation of MITF-M-dependent genes involved in pigmentation / ERK/MAPK targets / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / ADP signalling through P2Y purinoceptor 1 / Oxidative Stress Induced Senescence ...p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / Regulation of MITF-M-dependent genes involved in pigmentation / ERK/MAPK targets / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / ADP signalling through P2Y purinoceptor 1 / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / Myogenesis / VEGFA-VEGFR2 Pathway / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / cartilage condensation / positive regulation of myoblast fusion / cellular response to UV-B / mitogen-activated protein kinase p38 binding / positive regulation of myotube differentiation / NFAT protein binding / D-glucose import / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / response to dietary excess / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / positive regulation of interleukin-12 production / Neutrophil degranulation / osteoclast differentiation / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / positive regulation of D-glucose import / stem cell differentiation / cellular response to ionizing radiation / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / cellular response to virus / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / MAPK cascade / cellular response to tumor necrosis factor / kinase activity / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / angiogenesis / transcription by RNA polymerase II / response to lipopolysaccharide / protein kinase activity / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / glutamatergic synapse / DNA damage response / regulation of DNA-templated transcription / positive regulation of gene expression / regulation of transcription by RNA polymerase II / apoptotic process / positive regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
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-OSZ / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.74100939272 Å
AuthorsJoerger, A.C. / Schroeder, M. / Roehm, S. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Eur.J.Med.Chem. / Year: 2020
Title: Selective targeting of the alpha C and DFG-out pocket in p38 MAPK.
Authors: Rohm, S. / Schroder, M. / Dwyer, J.E. / Widdowson, C.S. / Chaikuad, A. / Berger, B.T. / Joerger, A.C. / Kramer, A. / Harbig, J. / Dauch, D. / Kudolo, M. / Laufer, S. / Bagley, M.C. / Knapp, S.
History
DepositionApr 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 15, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 21, 2020Group: 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
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)42,0293
Polymers41,3951
Non-polymers6342
Water4,612256
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint2 kcal/mol
Surface area16610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.140, 70.290, 75.040
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 / MAPK 14 / CRK1 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha


Mass: 41395.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mapk14, Crk1, Csbp1, Csbp2 / Production host: Escherichia coli (E. coli)
References: UniProt: P47811, mitogen-activated protein kinase
#2: Chemical ChemComp-OSZ / 5-azanyl-~{N}-[[4-[[(2~{S})-4-cyclohexyl-1-oxidanylidene-1-piperazin-1-yl-butan-2-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide


Mass: 571.713 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H41N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.2 Å3/Da / Density % sol: 44.15 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 15% medium MW PEG SMEAR, 0.1 M MES, pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.3 / Wavelength: 0.89429 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Apr 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.89429 Å / Relative weight: 1
ReflectionResolution: 1.74→51.3 Å / Num. obs: 37702 / % possible obs: 99 % / Redundancy: 5.1 % / Biso Wilson estimate: 20.639945905 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.069 / Net I/σ(I): 11.3
Reflection shellResolution: 1.74→1.84 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.509 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 5295 / CC1/2: 0.767 / % possible all: 97.2

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LAR

5lar


Resolution: 1.74100939272→51.2996317086 Å / SU ML: 0.204132508553 / Cross valid method: FREE R-VALUE / σ(F): 1.33793257312 / Phase error: 21.3683944376
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.23655776934 1877 4.9863188375 %random
Rwork0.201633474773 35766 --
obs0.203212349275 37643 98.7046700055 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.2032747798 Å2
Refinement stepCycle: LAST / Resolution: 1.74100939272→51.2996317086 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2658 0 46 256 2960
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004278899114822790
X-RAY DIFFRACTIONf_angle_d0.7252336585383796
X-RAY DIFFRACTIONf_chiral_restr0.0466818908067425
X-RAY DIFFRACTIONf_plane_restr0.00470245383344484
X-RAY DIFFRACTIONf_dihedral_angle_d16.48700491111671
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7411-1.78810.3138023319881700.2683845623482569X-RAY DIFFRACTION94.8407202216
1.7881-1.84070.2487150304421670.2369510578132672X-RAY DIFFRACTION98.6791797011
1.8407-1.90010.2538553486691500.2313418578352710X-RAY DIFFRACTION98.6887508627
1.9001-1.9680.2653430925291260.2237695784022739X-RAY DIFFRACTION98.4874527329
1.968-2.04680.2764316506861260.2050707311852726X-RAY DIFFRACTION98.8904299584
2.0468-2.140.2340360551521330.2004128622822749X-RAY DIFFRACTION98.8001371272
2.14-2.25280.2785490824261630.2100609472452712X-RAY DIFFRACTION99.2063492063
2.2528-2.3940.2572325564451940.2101295907022708X-RAY DIFFRACTION99.1458831568
2.394-2.57880.2755689597191530.1984488210832753X-RAY DIFFRACTION99.3164730007
2.5788-2.83830.2275904323521490.1989859043412755X-RAY DIFFRACTION99.4180075317
2.8383-3.24890.2750197104281310.2046051878732822X-RAY DIFFRACTION99.4610980128
3.2489-4.09310.1886358027351030.1781762493452878X-RAY DIFFRACTION99.5657982632
4.0931-51.2990.1651206158811120.1964716796582973X-RAY DIFFRACTION98.6253196931

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