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- PDB-6y4u: Crystal structure of p38 in complex with SR65 -

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Basic information

Entry
Database: PDB / ID: 6y4u
TitleCrystal structure of p38 in complex with SR65
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 / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence ...p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence / ADP signalling through P2Y purinoceptor 1 / 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 / positive regulation of myoblast fusion / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / p38MAPK cascade / response to dietary excess / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / regulation of ossification / MAP kinase activity / cellular response to vascular endothelial growth factor stimulus / mitogen-activated protein kinase / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / 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 / striated muscle cell differentiation / response to muscle stretch / Neutrophil degranulation / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / positive regulation of D-glucose import / stem cell differentiation / negative regulation of canonical Wnt signaling pathway / response to insulin / bone development / cellular response to virus / positive regulation of protein import into nucleus / glucose metabolic process / cell morphogenesis / positive regulation of reactive oxygen species metabolic process / spindle pole / osteoblast differentiation / cellular response to tumor necrosis factor / kinase activity / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / protein phosphatase binding / response to lipopolysaccharide / transcription by RNA polymerase II / protein kinase activity / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / DNA damage response / positive regulation of gene expression / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / glutamatergic synapse / positive regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
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. / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-O98 / 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)42,2166
Polymers41,3951
Non-polymers8215
Water2,432135
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area780 Å2
ΔGint13 kcal/mol
Surface area16700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.019, 74.919, 77.799
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-O98 / 5-azanyl-~{N}-[[4-[[(2~{S})-4-cyclohexyl-1-oxidanylidene-1-(pentan-3-ylamino)butan-2-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide


Mass: 572.741 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H44N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 135 / 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: 47.07 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6.2 / Details: 17.5% 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 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→77.799 Å / Num. all: 32347 / Num. obs: 32347 / % possible obs: 97.9 % / Redundancy: 6 % / Rpim(I) all: 0.025 / Rrim(I) all: 0.062 / Rsym value: 0.057 / Net I/av σ(I): 6.1 / Net I/σ(I): 14.6 / Num. measured all: 194008
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
1.86-1.9660.8720.92740945980.3870.9560.872296.9
1.96-2.086.10.481.62657443850.210.5250.483.697.1
2.08-2.226.10.2682.82507341270.1170.2930.2686.297.6
2.22-2.460.1574.72293938490.0690.1720.1579.697.7
2.4-2.635.90.1017.12136135980.0450.1110.10113.698.4
2.63-2.946.10.079.51992032550.030.0760.0719.498.3
2.94-3.46.10.05211.31778629060.0230.0570.05226.498.5
3.4-4.1660.044131496324990.0190.0480.04433.899.1
4.16-5.885.90.042141159519640.0190.0460.04235.699.3
5.88-77.7995.50.04311.1638811660.020.0470.04334.399.5

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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→53.97 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.942 / SU B: 8.619 / SU ML: 0.124 / SU R Cruickshank DPI: 0.1427 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.143 / ESU R Free: 0.142
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2411 1670 5.2 %RANDOM
Rwork0.1897 ---
obs0.1924 30628 97.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 124.68 Å2 / Biso mean: 51.936 Å2 / Biso min: 25.74 Å2
Baniso -1Baniso -2Baniso -3
1-2.11 Å20 Å2-0 Å2
2---1.24 Å20 Å2
3----0.87 Å2
Refinement stepCycle: final / Resolution: 1.86→53.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2716 0 58 135 2909
Biso mean--47.45 51.02 -
Num. residues----341
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192865
X-RAY DIFFRACTIONr_bond_other_d0.0020.022746
X-RAY DIFFRACTIONr_angle_refined_deg1.6521.9573891
X-RAY DIFFRACTIONr_angle_other_deg0.93836308
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5215349
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.4824.06133
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.60915479
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4121518
X-RAY DIFFRACTIONr_chiral_restr0.1050.2435
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213322
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02664
LS refinement shellResolution: 1.86→1.908 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.333 136 -
Rwork0.332 2153 -
all-2289 -
obs--96.3 %
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)
13.6493-0.76650.69711.7325-1.0031.04470.0587-0.3014-0.25350.07090.01110.1951-0.0507-0.0768-0.06970.0344-0.0060.01540.07230.00850.2521-1.7961.72617.354
22.80420.0859-0.13281.4606-0.16420.25690.08530.0485-0.0173-0.0397-0.2083-0.23870.00840.12850.1230.00690.0063-0.00590.09710.08280.2317.0485.43414.265
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 201
2X-RAY DIFFRACTION2A202 - 355

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