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- PDB-6sfj: Crystal structure of p38 alpha in complex with compound 77 (MCP41) -

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Basic information

Entry
Database: PDB / ID: 6sfj
TitleCrystal structure of p38 alpha in complex with compound 77 (MCP41)
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE / p38a / MAPK / MAPK14 / kinase inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


positive regulation of cyclase activity / stress-activated protein kinase signaling cascade / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / DSCAM interactions ...positive regulation of cyclase activity / stress-activated protein kinase signaling cascade / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / DSCAM interactions / cartilage condensation / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / positive regulation of muscle cell differentiation / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / glucose import / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / MAP kinase kinase activity / response to dietary excess / response to muramyl dipeptide / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / signal transduction in response to DNA damage / 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 / negative regulation of inflammatory response to antigenic stimulus / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / placenta development / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / platelet activation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / protein phosphatase binding / secretory granule lumen / Oxidative Stress Induced Senescence / angiogenesis / Regulation of TP53 Activity through Phosphorylation / cellular response to lipopolysaccharide / 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 / glutamatergic synapse / apoptotic process / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / 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. / 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-LBB / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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)41,8972
Polymers41,3951
Non-polymers5021
Water3,261181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area17000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.339, 76.109, 78.950
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 / 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-LBB / ~{N}-[5-[[(2~{S})-1-azanyl-4-cyclohexyl-1-oxidanylidene-butan-2-yl]carbamoyl]-2-methyl-phenyl]-1-(2-methylphenyl)pyrazole-4-carboxamide


Mass: 501.620 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H35N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 181 / 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: 2.41 Å3/Da / Density % sol: 48.91 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6.2 / Details: 17.5% MMW PEG smears, 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: 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: 1.95→50.8 Å / Num. obs: 29720 / % possible obs: 99.7 % / Redundancy: 6.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.03 / Rrim(I) all: 0.08 / Net I/σ(I): 16.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.95-2.026.80.9242.228740.6550.4051.08699.8
7.55-50.796.30.0245880.9990.010.02698.3

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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: 1.95→50.8 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.942 / SU B: 8.167 / SU ML: 0.118 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.158 / ESU R Free: 0.147
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2267 1533 5.2 %RANDOM
Rwork0.1847 ---
obs0.1868 28135 99.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 114.95 Å2 / Biso mean: 40.521 Å2 / Biso min: 18.26 Å2
Baniso -1Baniso -2Baniso -3
1-1.28 Å20 Å2-0 Å2
2---1.53 Å20 Å2
3---0.25 Å2
Refinement stepCycle: final / Resolution: 1.95→50.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2736 0 37 181 2954
Biso mean--25.76 41.74 -
Num. residues----341
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0132882
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172672
X-RAY DIFFRACTIONr_angle_refined_deg1.3641.6363924
X-RAY DIFFRACTIONr_angle_other_deg1.2441.5926200
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7945351
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.4122.452155
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.1315491
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.671518
X-RAY DIFFRACTIONr_chiral_restr0.0660.2373
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.023312
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02606
LS refinement shellResolution: 1.95→2.001 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.31 136 -
Rwork0.283 2007 -
all-2143 -
obs--99.58 %
Refinement TLS params.Method: refined / Origin x: 6.8486 Å / Origin y: 42.0983 Å / Origin z: 16.2549 Å
111213212223313233
T0.0091 Å2-0.0022 Å20.0153 Å2-0.0137 Å20.0047 Å2--0.0347 Å2
L1.8257 °2-0.0689 °20.2216 °2-0.9244 °2-0.4119 °2--0.4122 °2
S0.0325 Å °-0.0783 Å °-0.0391 Å °0.035 Å °-0.0728 Å °0.0145 Å °0.0093 Å °0.0079 Å °0.0402 Å °

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