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- PDB-6y4v: Crystal structure of p38 in complex with SR68 -

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Basic information

Entry
Database: PDB / ID: 6y4v
TitleCrystal structure of p38 in complex with SR68
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE / kinase / kinase inhibitor / MAPK14 / MAPK / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


DSCAM interactions / p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / ADP signalling through P2Y purinoceptor 1 / Oxidative Stress Induced Senescence ...DSCAM interactions / p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / 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 / cellular response to UV-B / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / glucose import / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / response to dietary excess / response to muramyl dipeptide / MAP kinase activity / regulation of ossification / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / positive regulation of cardiac muscle cell proliferation / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / Neutrophil degranulation / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / placenta development / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / 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 / protein phosphatase binding / angiogenesis / cellular response to lipopolysaccharide / 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 / glutamatergic synapse / apoptotic process / DNA damage response / regulation of DNA-templated transcription / positive regulation of gene expression / regulation of transcription by RNA polymerase II / 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. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-O8Z / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 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)42,46410
Polymers41,3951
Non-polymers1,0699
Water3,171176
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1480 Å2
ΔGint22 kcal/mol
Surface area16890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.779, 74.880, 77.690
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 / MAPK14 / 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-O8Z / 5-azanyl-~{N}-[[4-[[(2~{S})-4-cyclohexyl-1-(3-methylbutylamino)-1-oxidanylidene-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 / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 176 / 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: 46.78 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 20% 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: Jan 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.75→65.779 Å / Num. all: 39442 / Num. obs: 39442 / % possible obs: 100 % / Redundancy: 5.9 % / Rpim(I) all: 0.032 / Rrim(I) all: 0.077 / Rsym value: 0.07 / Net I/av σ(I): 3.8 / Net I/σ(I): 12.8 / Num. measured all: 233179
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
1.75-1.845.70.651.23240456750.2960.7160.652.6100
1.84-1.965.90.37923171053760.170.4160.3794.4100
1.96-2.0960.2123.33012550550.0940.2320.2127.3100
2.09-2.2660.13152849447370.0590.1440.13111.1100
2.26-2.4760.0956.52594643490.0430.1050.09514.4100
2.47-2.7760.0777.22365939760.0350.0840.07717.6100
2.77-3.26.10.0716.62126835060.0320.0780.07121.4100
3.2-3.9160.0657.31817930120.0290.0710.06524.7100
3.91-5.535.80.0618.71367023650.0280.0680.06125.5100
5.53-65.7795.60.067.7772413910.0280.0660.0624.899.9

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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: 1.75→53.91 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.955 / SU B: 5.917 / SU ML: 0.095 / SU R Cruickshank DPI: 0.1161 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.116 / ESU R Free: 0.112
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2216 1995 5.1 %RANDOM
Rwork0.1895 ---
obs0.1912 37387 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 126.74 Å2 / Biso mean: 49.729 Å2 / Biso min: 23.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.64 Å2-0 Å2-0 Å2
2---1.6 Å20 Å2
3---0.96 Å2
Refinement stepCycle: final / Resolution: 1.75→53.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2733 0 74 176 2983
Biso mean--45.27 48.78 -
Num. residues----343
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192888
X-RAY DIFFRACTIONr_bond_other_d0.0020.022772
X-RAY DIFFRACTIONr_angle_refined_deg1.6431.9583913
X-RAY DIFFRACTIONr_angle_other_deg0.96736364
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0645349
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.38723.985133
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.91915478
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5211518
X-RAY DIFFRACTIONr_chiral_restr0.1040.2436
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0213331
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02667
LS refinement shellResolution: 1.75→1.795 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 143 -
Rwork0.294 2726 -
all-2869 -
obs--99.97 %
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)
13.2347-0.52880.4071.8276-1.15531.07280.0902-0.2567-0.41080.05830.03980.318-0.0334-0.0959-0.130.0342-0.00430.00960.04570.02360.1541-3.91190.393417.5528
27.95510.90952.95546.30652.32691.7505-0.4953-0.4191.4134-0.47620.0735-0.2377-0.4061-0.1390.42180.47740.10020.02160.21880.11350.490614.264412.522817.034
33.3055-0.0187-0.16751.646-0.5150.41750.1280.0835-0.0412-0.0375-0.2893-0.2541-0.0160.18380.16130.00760.0014-0.0030.09130.07560.073817.04875.48514.3713
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 170
2X-RAY DIFFRACTION2A171 - 202
3X-RAY DIFFRACTION3A203 - 355

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