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- PDB-6y4t: Crystal structure of p38 in complex with SR63. -

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Basic information

Entry
Database: PDB / ID: 6y4t
TitleCrystal structure of p38 in complex with SR63.
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / kinase / kinase inhibitor / MAPK / 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-O8W / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.98 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 1.1Apr 15, 2020Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.2Jan 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 1.3Jan 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)42,3889
Polymers41,3951
Non-polymers9938
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1470 Å2
ΔGint22 kcal/mol
Surface area16590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.079, 75.030, 77.890
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-O8W / 5-azanyl-~{N}-[[4-[[(2~{S})-1-[[(2~{S})-butan-2-yl]amino]-4-cyclohexyl-1-oxidanylidene-butan-2-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide


Mass: 558.714 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H42N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 131 / 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: 2.33 Å3/Da / Density % sol: 47.26 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 12% PEG Smear Medium, 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: Nov 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.98→54.04 Å / Num. obs: 27680 / % possible obs: 100 % / Redundancy: 5.9 % / Rpim(I) all: 0.033 / Rrim(I) all: 0.08 / Rsym value: 0.073 / Net I/av σ(I): 6.5 / Net I/σ(I): 11.6
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
1.98-2.095.80.8290.92327139900.3720.9110.8292.1100
2.09-2.2160.4961.52256137780.2190.5430.4963.3100
2.21-2.375.80.3192.42035235320.1450.3510.3194.8100
2.37-2.565.90.2153.41960233120.0960.2350.2156.9100
2.56-2.860.14151834030450.0620.1540.14110.1100
2.8-3.1360.0956.81668627970.0430.1050.09514.9100
3.13-3.6160.062101468024580.0280.0680.06221.8100
3.61-4.435.90.05111.81257221170.0230.0560.05128.1100
4.43-6.265.80.04612.4965216690.0210.0510.04628.2100
6.26-54.0375.40.03713.952689820.0180.0410.03728.499.8

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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: 1.98→54.04 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.941 / SU B: 11.046 / SU ML: 0.15 / SU R Cruickshank DPI: 0.18 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.18 / ESU R Free: 0.169
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2508 1481 5.4 %RANDOM
Rwork0.1983 ---
obs0.201 26143 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 112.34 Å2 / Biso mean: 49.84 Å2 / Biso min: 26.59 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å20 Å20 Å2
2--1.48 Å2-0 Å2
3----1.01 Å2
Refinement stepCycle: final / Resolution: 1.98→54.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2706 0 69 131 2906
Biso mean--47.09 49.94 -
Num. residues----341
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0192857
X-RAY DIFFRACTIONr_bond_other_d0.0020.022738
X-RAY DIFFRACTIONr_angle_refined_deg1.5871.9573875
X-RAY DIFFRACTIONr_angle_other_deg0.93436281
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.435346
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.49823.969131
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.24515470
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1821518
X-RAY DIFFRACTIONr_chiral_restr0.0960.2434
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213305
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02661
LS refinement shellResolution: 1.98→2.031 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.316 95 -
Rwork-1916 -
obs--99.9 %
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)
13.04-0.47520.53591.1911-0.8940.69990.0524-0.2108-0.29910.02150.03990.19150.01-0.0505-0.09230.3636-0.01760.01910.01840.0010.4158-3.8490.59917.525
26.36240.60943.29521.62730.66852.1686-0.54090.0641.1101-0.3328-0.0758-0.1891-0.44210.10120.61670.55190.00370.04070.05520.14570.609316.79612.31314.897
32.5111-0.12380.27011.2724-0.26020.59420.05620.0184-0.00280.0121-0.1507-0.1950.01150.07370.09460.3356-0.00250.00860.02330.05210.336417.4565.92214.449
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 183
2X-RAY DIFFRACTION2A184 - 203
3X-RAY DIFFRACTION3A204 - 355

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