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- PDB-6y4w: Crystal structure of p38 in complex with SR69 -

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Basic information

Entry
Database: PDB / ID: 6y4w
TitleCrystal structure of p38 in complex with SR69
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-O8T / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 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

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,2907
Polymers41,3951
Non-polymers8956
Water2,774154
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1090 Å2
ΔGint14 kcal/mol
Surface area16440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.059, 74.980, 77.710
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-O8T / 5-azanyl-~{N}-[[4-[[(2~{S})-4-cyclohexyl-1-(cyclohexylamino)-1-oxidanylidene-butan-2-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide


Mass: 584.752 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H44N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 154 / 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: 2.32 Å3/Da / Density % sol: 47.09 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 25% PEG Smear Broad, 0.1M MES pH 6.0

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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 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: 1.86→77.71 Å / Num. all: 33145 / Num. obs: 33145 / % possible obs: 100 % / Redundancy: 6 % / Rpim(I) all: 0.025 / Rrim(I) all: 0.061 / Rsym value: 0.055 / Net I/av σ(I): 6.8 / Net I/σ(I): 15 / Num. measured all: 199656
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
1.86-1.9660.8670.82845747700.3850.9510.8672.1100
1.96-2.086.10.4961.52739445170.2180.5430.4963.7100
2.08-2.226.10.2812.62587242490.1240.3080.2816.3100
2.22-2.460.1624.52360439500.0720.1780.1629.5100
2.4-2.6360.1056.92203036760.0470.1150.10513.4100
2.63-2.946.10.0719.52029733210.0310.0780.07119100
2.94-3.46.20.0512.51833029610.0220.0550.0527.2100
3.4-4.1660.03815.51523425280.0170.0420.03836.3100
4.16-5.8860.037161194619950.0160.0410.03739.1100
5.88-77.715.50.04111.7649211780.0190.0460.04137.699.9

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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: 1.86→53.96 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.946 / SU B: 7.671 / SU ML: 0.114 / SU R Cruickshank DPI: 0.1379 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.138 / ESU R Free: 0.135
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2328 1713 5.2 %RANDOM
Rwork0.1881 ---
obs0.1904 31369 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 115.12 Å2 / Biso mean: 51.161 Å2 / Biso min: 25.67 Å2
Baniso -1Baniso -2Baniso -3
1-2.05 Å20 Å2-0 Å2
2---2.22 Å20 Å2
3---0.17 Å2
Refinement stepCycle: final / Resolution: 1.86→53.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2713 0 63 154 2930
Biso mean--45.84 49.54 -
Num. residues----341
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192848
X-RAY DIFFRACTIONr_bond_other_d0.0020.022735
X-RAY DIFFRACTIONr_angle_refined_deg1.661.9553861
X-RAY DIFFRACTIONr_angle_other_deg0.95436280
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2795343
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.48723.876129
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.59915474
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.9031518
X-RAY DIFFRACTIONr_chiral_restr0.1020.2432
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213257
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02653
LS refinement shellResolution: 1.86→1.908 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.29 137 -
Rwork0.323 2241 -
all-2378 -
obs--99.87 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.1673-0.8470.18072.058-1.91192.14890.0827-0.1991-0.45680.0730.22780.4956-0.1447-0.2837-0.31050.033-0.00190.00870.14390.03990.3056-10.21342.201817.1112
24.4864-0.51141.80011.75830.57912.2492-0.0557-0.14120.06640.1045-0.1794-0.026-0.03240.00370.23510.0943-0.01860.02690.1260.04110.146213.19191.671518.8616
33.1761-0.57710.38321.6036-0.43220.86890.01280.18950.08120.0115-0.1821-0.24510.020.17490.16930.00150.00240.00680.09540.06280.108816.78465.910512.8329
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 120
2X-RAY DIFFRACTION2A121 - 224
3X-RAY DIFFRACTION3A225 - 355

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