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- PDB-5tco: Human p38 MAP Kinase in Complex with Dibenzosuberone Compound 1 -

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Basic information

Entry
Database: PDB / ID: 5tco
TitleHuman p38 MAP Kinase in Complex with Dibenzosuberone Compound 1
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / Inhibitor / Dibenzosuberone / Human p38 MAP Kinase
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 / cartilage condensation ...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 / cartilage condensation / DSCAM interactions / 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 / regulation of cytokine production involved in inflammatory response / ERK/MAPK targets / 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 / cellular response to vascular endothelial growth factor stimulus / mitogen-activated protein kinase / signal transduction in response to DNA damage / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / 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 / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / placenta development / 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 / chemotaxis / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / peptidyl-serine phosphorylation / protein phosphatase binding / angiogenesis / secretory granule lumen / 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 / 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. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-79Q / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsMayer-Wrangowski, S.C. / Rauh, D.
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2017
Title: Optimized Target Residence Time: Type I1/2 Inhibitors for p38 alpha MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine.
Authors: Wentsch, H.K. / Walter, N.M. / Buhrmann, M. / Mayer-Wrangowski, S. / Rauh, D. / Zaman, G.J.R. / Willemsen-Seegers, N. / Buijsman, R.C. / Henning, M. / Dauch, D. / Zender, L. / Laufer, S.
History
DepositionSep 15, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 19, 2017Provider: repository / Type: Initial release
Revision 1.1May 3, 2017Group: Database references
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.name ..._chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3May 8, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
Item: _chem_comp.pdbx_synonyms / _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)42,4464
Polymers41,2691
Non-polymers1,1773
Water1,04558
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1410 Å2
ΔGint13 kcal/mol
Surface area16080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.070, 69.750, 74.730
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: 41269.055 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 / Production host: Escherichia coli (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-79Q / 3-[(3-benzamido-4-fluoranyl-phenyl)amino]-~{N}-(2-morpholin-4-ylethyl)-11-oxidanylidene-5,6-dihydrodibenzo[1,2-~{d}:1',2'-~{f}][7]annulene-9-carboxamide


Mass: 592.659 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H33FN4O4
#3: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 58 / Source method: isolated from a natural source / Formula: H2O

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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: 2.29 Å3/Da / Density % sol: 46.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.2 / Details: 100 mM MES, 22% PEG4000, 50 mM n-BOG

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 6, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 20751 / % possible obs: 99.9 % / Redundancy: 6.51 % / Rrim(I) all: 0.077 / Net I/σ(I): 21.65
Reflection shellResolution: 2.1→2.2 Å / Mean I/σ(I) obs: 6.09 / Rrim(I) all: 0.402 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→47.97 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.895 / SU B: 6.064 / SU ML: 0.162 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.257 / ESU R Free: 0.215
RfactorNum. reflection% reflectionSelection details
Rfree0.2697 1038 5 %RANDOM
Rwork0.2145 ---
obs0.2172 19713 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 79.49 Å2 / Biso min: 13.07 Å2
Baniso -1Baniso -2Baniso -3
1-1.25 Å2-0 Å20 Å2
2--0.24 Å20 Å2
3----1.5 Å2
Refinement stepCycle: final / Resolution: 2.1→47.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2600 0 84 58 2742
Biso mean--33.36 26.47 -
Num. residues----327
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.022747
X-RAY DIFFRACTIONr_bond_other_d0.0060.022627
X-RAY DIFFRACTIONr_angle_refined_deg1.8172.0013731
X-RAY DIFFRACTIONr_angle_other_deg0.9663.0095963
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.335323
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.6924.167120
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.215450
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.691515
X-RAY DIFFRACTIONr_chiral_restr0.0990.2425
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213013
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02618
X-RAY DIFFRACTIONr_mcbond_it2.272.6331304
X-RAY DIFFRACTIONr_mcbond_other2.2662.631303
X-RAY DIFFRACTIONr_mcangle_it3.3543.9291623
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.246 75 -
Rwork0.235 1420 -
all-1495 -
obs--99.93 %

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