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- PDB-6y6v: p38a bound with MCP-81 -

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Basic information

Entry
Database: PDB / ID: 6y6v
Titlep38a bound with MCP-81
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / Kinase / Inhibitor / 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 / 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 / cartilage condensation / cellular response to UV-B / 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 / 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 / JUN kinase activity / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / positive regulation of myoblast differentiation / vascular endothelial growth factor receptor signaling pathway / skeletal muscle tissue development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / 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 / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / positive regulation of D-glucose import / stem cell differentiation / response to insulin / placenta development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / bone development / cellular response to virus / positive regulation of protein import into nucleus / glucose metabolic process / spindle pole / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / kinase activity / MAPK cascade / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / angiogenesis / 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 / 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. / : / 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-OE5 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsSchroeder, M. / Roehm, S. / Knapp, S. / Arrowsmith, C.H. / Bountra, C. / Edwards, A.M. / 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 27, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 11, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Oct 21, 2020Group: 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_PubMed / _citation.title
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)41,9432
Polymers41,3951
Non-polymers5481
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.230, 72.680, 77.060
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 (E. coli)
References: UniProt: P47811, mitogen-activated protein kinase
#2: Chemical ChemComp-OE5 / 5-azanyl-~{N}-[[4-[[5-~{tert}-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide / MCP-81


Mass: 547.650 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H33N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 2.24 Å3/Da / Density % sol: 45.09 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 15% MWW PegSmear 0.1 M MES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.3 / Wavelength: 0.89429 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Apr 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.89429 Å / Relative weight: 1
ReflectionResolution: 2.1→50.28 Å / Num. obs: 22199 / % possible obs: 99.5 % / Redundancy: 5 % / CC1/2: 0.982 / Rmerge(I) obs: 0.158 / Rpim(I) all: 0.077 / Rrim(I) all: 0.176 / Net I/σ(I): 6.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.1-2.165.10.875921918010.5720.4270.9781.699.2
8.91-50.233.40.06611373370.9270.0470.08212.398.7

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LAR

5lar


Resolution: 2.1→50.28 Å / Cor.coef. Fo:Fc: 0.878 / Cor.coef. Fo:Fc free: 0.849 / SU B: 16.29 / SU ML: 0.21 / SU R Cruickshank DPI: 0.2978 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.298 / ESU R Free: 0.243
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.3038 1039 4.7 %RANDOM
Rwork0.2487 ---
obs0.2514 20842 97.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 61.61 Å2 / Biso mean: 27.102 Å2 / Biso min: 10.28 Å2
Baniso -1Baniso -2Baniso -3
1--1.43 Å2-0 Å2-0 Å2
2---0.22 Å20 Å2
3---1.66 Å2
Refinement stepCycle: final / Resolution: 2.1→50.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2636 0 41 188 2865
Biso mean--25.95 33.28 -
Num. residues----331
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0132767
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172539
X-RAY DIFFRACTIONr_angle_refined_deg1.6711.6333770
X-RAY DIFFRACTIONr_angle_other_deg1.3091.5895865
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.75331
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.02222.378143
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.64815450
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.4341516
X-RAY DIFFRACTIONr_chiral_restr0.0720.2358
X-RAY DIFFRACTIONr_gen_planes_refined0.010.023246
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02590
LS refinement shellResolution: 2.1→2.154 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 77 -
Rwork0.281 1533 -
all-1610 -
obs--98.83 %
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)
13.4885-1.6921-1.16911.92260.43331.65540.11540.26650.1689-0.3022-0.17310.1106-0.1509-0.44330.05770.2522-0.0017-0.00030.1952-0.06680.08674.402532.27320.7923
22.72851.4585-0.73311.9822-1.40632.91710.0782-0.13540.14730.0596-0.08650.0997-0.2589-0.13260.00830.19920.0302-0.01280.0279-0.00890.024330.934735.439418.4294
32.44140.3059-0.09730.70250.10971.93480.09830.0657-0.07820.0263-0.0889-0.08340.05640.1071-0.00940.25510.0497-0.04690.0377-0.00760.032132.717627.632714.862
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 108
2X-RAY DIFFRACTION2A109 - 236
3X-RAY DIFFRACTION3A237 - 353

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