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- PDB-5n68: Crystal Structure of p38alpha in Complex with Lipid Pocket Ligand 9m -

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Basic information

Entry
Database: PDB / ID: 5n68
TitleCrystal Structure of p38alpha in Complex with Lipid Pocket Ligand 9m
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 / 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 ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / 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 myoblast fusion / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / D-glucose import / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / p38MAPK cascade / Regulation of MITF-M-dependent genes involved in pigmentation / fatty acid oxidation / MAP kinase kinase activity / cellular response to lipoteichoic acid / response to muramyl dipeptide / response to dietary excess / MAP kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / positive regulation of erythrocyte differentiation / osteoclast differentiation / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / positive regulation of D-glucose import / stem cell differentiation / cellular response to ionizing radiation / negative regulation of inflammatory response to antigenic stimulus / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / chemotaxis / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / 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 / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / apoptotic process / 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 ...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-8OK / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.85 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)41,7692
Polymers41,3431
Non-polymers4261
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.240, 74.980, 78.860
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-8OK / 2-(4-morpholin-4-ylphenyl)-~{N}4-(2-phenylethyl)quinazoline-4,7-diamine


Mass: 425.525 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 161 / 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: 2.37 Å3/Da / Density % sol: 48.16 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES pH 5.6-6.2 20-30 % PEG4000 50 mM BOG

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9786 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 19, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 34201 / % possible obs: 100 % / Redundancy: 13.1 % / Rrim(I) all: 0.05 / Net I/σ(I): 26.89
Reflection shellResolution: 1.85→1.95 Å / Redundancy: 13.2 % / Mean I/σ(I) obs: 3.05 / Rrim(I) all: 0.86 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementStarting model: 4DLI

4dli


Resolution: 1.85→42.012 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 24.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2203 1710 5 %RANDOM
Rwork0.1977 ---
obs0.1987 34201 99.98 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→42.012 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2661 0 32 161 2854
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082757
X-RAY DIFFRACTIONf_angle_d0.9043739
X-RAY DIFFRACTIONf_dihedral_angle_d9.8571653
X-RAY DIFFRACTIONf_chiral_restr0.056415
X-RAY DIFFRACTIONf_plane_restr0.006474
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.90450.38891410.34652683X-RAY DIFFRACTION100
1.9045-1.96590.28791380.26792639X-RAY DIFFRACTION100
1.9659-2.03620.2411400.23192655X-RAY DIFFRACTION100
2.0362-2.11770.23751420.20962690X-RAY DIFFRACTION100
2.1177-2.21410.20191410.21242682X-RAY DIFFRACTION100
2.2141-2.33080.2671410.21052679X-RAY DIFFRACTION100
2.3308-2.47680.21521410.21862676X-RAY DIFFRACTION100
2.4768-2.6680.23741430.21632713X-RAY DIFFRACTION100
2.668-2.93650.22261420.2222704X-RAY DIFFRACTION100
2.9365-3.36120.25361430.21332722X-RAY DIFFRACTION100
3.3612-4.23420.20281460.17772760X-RAY DIFFRACTION100
4.2342-42.02240.19361520.17162888X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -6.5913 Å / Origin y: -3.9565 Å / Origin z: 15.7535 Å
111213212223313233
T0.2985 Å20.018 Å2-0.0482 Å2-0.2026 Å2-0.0336 Å2--0.2027 Å2
L3.7008 °2-0.2531 °2-0.5556 °2-1.9815 °2-0.1644 °2--2.1865 °2
S0.0278 Å °-0.2215 Å °0.07 Å °0.1933 Å °-0.0947 Å °-0.0669 Å °0.0501 Å °0.1188 Å °0.0534 Å °
Refinement TLS groupSelection details: (chain A and resseq 4:351)

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