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- PDB-5n63: Crystal Structure of p38alpha in Complex with Lipid Pocket Ligand 9c -

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Basic information

Entry
Database: PDB / ID: 5n63
TitleCrystal Structure of p38alpha in Complex with Lipid Pocket Ligand 9c
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / kinase / small molecule / lipid pocket / p38 / quinazoline
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 / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion ...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 / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of myoblast fusion / 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 / response to dietary excess / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / Regulation of MITF-M-dependent genes involved in pigmentation / MAP kinase kinase activity / signal transduction in response to DNA damage / regulation of ossification / MAP kinase activity / 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 / striated muscle cell differentiation / response to muscle stretch / 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 / cellular response to ionizing radiation / positive regulation of D-glucose import / 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 / cell morphogenesis / positive regulation of reactive oxygen species metabolic process / chemotaxis / spindle pole / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / cellular senescence / 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. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-8OW / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsBuehrmann, M. / Mueller, M.P. / Rauh, D.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Federal Ministry for Education and Research (NGFNPlus and e:Med)BMBF 01GS08104, 01ZX1303C Germany
CitationJournal: PLoS ONE / Year: 2017
Title: Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38 alpha MAPK.
Authors: Buhrmann, M. / Wiedemann, B.M. / Muller, M.P. / Hardick, J. / Ecke, M. / Rauh, D.
History
DepositionFeb 14, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 20, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2019Group: Data collection / Category: reflns / reflns_shell
Item: _reflns.pdbx_Rrim_I_all / _reflns_shell.pdbx_Rrim_I_all
Revision 1.2Jan 17, 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)41,6882
Polymers41,3431
Non-polymers3441
Water57632
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.390, 74.900, 78.320
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 41343.195 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-8OW / ~{N}4-[(4-fluorophenyl)methyl]-2-phenyl-quinazoline-4,7-diamine


Mass: 344.385 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17FN4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.31 Å3/Da / Density % sol: 46.78 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES pH 5.6-6.2, 20-30 % PEG4000

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9779 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 26, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9779 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 15592 / % possible obs: 100 % / Redundancy: 13 % / Rrim(I) all: 0.081 / Net I/σ(I): 21.5
Reflection shellResolution: 2.4→2.5 Å / Redundancy: 13.6 % / Mean I/σ(I) obs: 2.76 / Rrim(I) all: 1.142 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DLI

4dli


Resolution: 2.4→49.259 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2282 780 5 %RANDOM
Rwork0.1946 ---
obs0.1963 15592 99.96 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→49.259 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2638 0 26 32 2696
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082727
X-RAY DIFFRACTIONf_angle_d0.9123703
X-RAY DIFFRACTIONf_dihedral_angle_d10.6691640
X-RAY DIFFRACTIONf_chiral_restr0.051415
X-RAY DIFFRACTIONf_plane_restr0.006469
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.55040.28831280.26992427X-RAY DIFFRACTION100
2.5504-2.74730.27781270.24772421X-RAY DIFFRACTION100
2.7473-3.02370.30511290.22832445X-RAY DIFFRACTION100
3.0237-3.46120.2771280.23092434X-RAY DIFFRACTION100
3.4612-4.36030.22911310.17512495X-RAY DIFFRACTION100
4.3603-49.26940.1821370.16892590X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -6.5305 Å / Origin y: -3.7389 Å / Origin z: 15.5731 Å
111213212223313233
T0.4113 Å20.0422 Å2-0.0536 Å2-0.345 Å2-0.0495 Å2--0.2776 Å2
L2.9034 °20.0821 °2-0.4045 °2-2.2198 °20.3909 °2--1.4443 °2
S0.0341 Å °-0.2209 Å °0.111 Å °0.1272 Å °-0.0435 Å °-0.1145 Å °0.0023 Å °0.0502 Å °0.0001 Å °
Refinement TLS groupSelection details: (chain A and resseq 5:353)

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