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- PDB-6y4x: Crystal structure of p38 in complex with SR72 -

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Basic information

Entry
Database: PDB / ID: 6y4x
TitleCrystal structure of p38 in complex with SR72
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / kinase / kinase inhibitor / MAPK14 / MAPK / 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-O8Q / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsChaikuad, A. / Roehm, S. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / 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
DepositionFeb 23, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: 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)42,4719
Polymers41,3951
Non-polymers1,0768
Water6,954386
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.819, 73.999, 77.299
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 / 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 BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: P47811, mitogen-activated protein kinase
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-O8Q / 5-azanyl-~{N}-[[4-[[(2~{S})-1-[2-(4-chlorophenyl)ethylamino]-4-cyclohexyl-1-oxidanylidene-butan-2-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide


Mass: 641.202 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H41ClN6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 386 / 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: 2.31 Å3/Da / Density % sol: 46.71 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6.2 / Details: 12% PEG Smear Medium, 0.1M MES pH 6.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jan 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.6→77.299 Å / Num. all: 51248 / Num. obs: 51248 / % possible obs: 99.9 % / Redundancy: 5.4 % / Rpim(I) all: 0.023 / Rrim(I) all: 0.054 / Rsym value: 0.049 / Net I/av σ(I): 8.5 / Net I/σ(I): 17.2 / Num. measured all: 275295
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
1.6-1.693.20.3082.52316473100.20.370.3083.499.4
1.69-1.794.90.2333.33444670010.1160.2610.2335.8100
1.79-1.915.90.164.63904866190.0720.1750.169.3100
1.91-2.075.90.1076.53607861390.0480.1180.10713.5100
2.07-2.265.90.088.33331056630.0360.0880.0818.6100
2.26-2.535.90.0649.93032351590.0290.0710.06422100
2.53-2.925.90.05112.12705145790.0230.0570.05126.7100
2.92-3.5860.03815.52362439110.0170.0420.03835.2100
3.58-5.0660.03417.41839530750.0150.0370.03441.6100
5.06-77.2995.50.03713.4985617920.0170.0410.03737.499.9

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
REFMAC5.8.0131refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5lar

5lar


Resolution: 1.6→53.45 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.951 / SU B: 3.194 / SU ML: 0.059 / SU R Cruickshank DPI: 0.0848 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.085 / ESU R Free: 0.088
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2043 2606 5.1 %RANDOM
Rwork0.1683 ---
obs0.1702 48572 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 68.78 Å2 / Biso mean: 26.665 Å2 / Biso min: 11.59 Å2
Baniso -1Baniso -2Baniso -3
1-1.24 Å20 Å20 Å2
2---0.3 Å20 Å2
3----0.93 Å2
Refinement stepCycle: final / Resolution: 1.6→53.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2835 0 74 388 3297
Biso mean--25.27 34.07 -
Num. residues----351
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193044
X-RAY DIFFRACTIONr_bond_other_d0.0030.022936
X-RAY DIFFRACTIONr_angle_refined_deg1.6031.9574129
X-RAY DIFFRACTIONr_angle_other_deg0.93936764
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7785371
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.08724.138145
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.48315533
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.6371520
X-RAY DIFFRACTIONr_chiral_restr0.1040.2453
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213550
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02706
LS refinement shellResolution: 1.6→1.642 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.253 180 -
Rwork0.228 3510 -
all-3690 -
obs--98.77 %
Refinement TLS params.Method: refined / Origin x: 31.134 Å / Origin y: 3.742 Å / Origin z: 13.242 Å
111213212223313233
T0.0066 Å2-0.013 Å2-0.0064 Å2-0.0494 Å2-0.0156 Å2--0.1101 Å2
L0.5646 °2-0.0741 °2-0.3532 °2-0.8191 °20.2583 °2--1.7679 °2
S0.0002 Å °0.0021 Å °0.0222 Å °-0.0237 Å °0.0631 Å °-0.0716 Å °-0.0631 Å °0.1936 Å °-0.0633 Å °

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