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- PDB-6sfk: Crystal structure of p38 alpha in complex with compound 81 (MCP42) -

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Basic information

Entry
Database: PDB / ID: 6sfk
TitleCrystal structure of p38 alpha in complex with compound 81 (MCP42)
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / p38a / MAPK / MAPK14 / kinase inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / CD163 mediating an anti-inflammatory response / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / cellular response to UV-B / cartilage condensation / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / D-glucose import / p38MAPK cascade / ERK/MAPK targets / fatty acid oxidation / cellular response to lipoteichoic acid / response to dietary excess / response to muramyl dipeptide / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / signal transduction in response to DNA damage / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / RHO GTPases Activate NADPH Oxidases / 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 / p38MAPK events / positive regulation of brown fat cell differentiation / response to muscle stretch / striated muscle cell differentiation / 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 / positive regulation of D-glucose import across plasma membrane / cellular response to ionizing radiation / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / response to insulin / bone development / cellular response to virus / platelet activation / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cell morphogenesis / chemotaxis / spindle pole / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / MAPK cascade / cellular response to lipopolysaccharide / angiogenesis / secretory granule lumen / protein phosphatase binding / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / transcription by RNA polymerase II / cell surface receptor signaling pathway / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / glutamatergic synapse / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular region / nucleoplasm / ATP binding
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-LB8 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsChaikuad, A. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2019
Title: Fast Iterative Synthetic Approach toward Identification of Novel Highly Selective p38 MAP Kinase Inhibitors.
Authors: Rohm, S. / Berger, B.T. / Schroder, M. / Chaikuad, A. / Winkel, R. / Hekking, K.F.W. / Benningshof, J.J.C. / Muller, G. / Tesch, R. / Kudolo, M. / Forster, M. / Laufer, S. / Knapp, S.
History
DepositionAug 1, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 11, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 29, 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_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)42,1996
Polymers41,3951
Non-polymers8045
Water3,837213
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area850 Å2
ΔGint13 kcal/mol
Surface area16670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.689, 76.250, 78.530
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 / Cytokine suppressive anti-inflammatory drug-binding protein / CSBP / MAP kinase MXI2 / ...MAPK 14 / Cytokine suppressive anti-inflammatory drug-binding protein / CSBP / MAP kinase MXI2 / MAX-interacting protein 2 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Stress-activated protein kinase 2a / SAPK2a


Mass: 41395.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2, SAPK2A / Plasmid: pET-Duet1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-LB8 / ~{N}-[5-[[(2~{S})-1-azanyl-4-cyclohexyl-1-oxidanylidene-butan-2-yl]carbamoyl]-2-methyl-phenyl]-1-phenyl-5-(trifluoromethyl)pyrazole-4-carboxamide


Mass: 555.591 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H32F3N5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 213 / 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: 2.38 Å3/Da / Density % sol: 48.22 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 17.5% MMW PEG smears, 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: I04-1 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Feb 26, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 1.8→50.4 Å / Num. obs: 37064 / % possible obs: 99.6 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.026 / Rrim(I) all: 0.063 / Net I/σ(I): 14.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.8-1.866.30.7482.435780.7530.3380.88999.6
6.97-50.396.80.0317370.9980.0130.03399.4

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LAR

5lar


Resolution: 1.8→50.4 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.948 / SU B: 5.4 / SU ML: 0.086 / SU R Cruickshank DPI: 0.1194 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.119 / ESU R Free: 0.117
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2184 1799 4.9 %RANDOM
Rwork0.1806 ---
obs0.1825 35211 99.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 93.43 Å2 / Biso mean: 37.609 Å2 / Biso min: 17.36 Å2
Baniso -1Baniso -2Baniso -3
1-0.58 Å20 Å2-0 Å2
2---1.05 Å20 Å2
3---0.46 Å2
Refinement stepCycle: final / Resolution: 1.8→50.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2726 0 56 213 2995
Biso mean--31.91 41.57 -
Num. residues----339
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0132866
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172666
X-RAY DIFFRACTIONr_angle_refined_deg1.4841.6393891
X-RAY DIFFRACTIONr_angle_other_deg1.2981.596179
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6885343
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.8722.303152
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.11415485
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8971518
X-RAY DIFFRACTIONr_chiral_restr0.0740.2369
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.023261
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02601
LS refinement shellResolution: 1.8→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 124 -
Rwork0.265 2548 -
all-2672 -
obs--99.48 %
Refinement TLS params.Method: refined / Origin x: 6.74 Å / Origin y: 42.109 Å / Origin z: 16.04 Å
111213212223313233
T0.0053 Å20.0016 Å20.0192 Å2-0.0155 Å20.0175 Å2--0.0927 Å2
L1.7432 °2-0.2113 °20.2404 °2-0.7899 °2-0.3126 °2--0.3462 °2
S0.0302 Å °-0.0697 Å °-0.0569 Å °0.0114 Å °-0.0621 Å °0.0237 Å °0.0054 Å °0.0108 Å °0.0319 Å °

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