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- PDB-5n64: Crystal Structure of p38alpha in Complex with Lipid Pocket Ligand 9g -

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Basic information

Entry
Database: PDB / ID: 5n64
TitleCrystal Structure of p38alpha in Complex with Lipid Pocket Ligand 9g
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 / fatty acid oxidation / response to dietary excess / cellular response to lipoteichoic acid / 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 / positive regulation of erythrocyte differentiation / osteoclast differentiation / lipopolysaccharide-mediated signaling pathway / DNA damage checkpoint signaling / placenta development / tumor necrosis factor-mediated signaling pathway / positive regulation of D-glucose import / 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. / : / 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-8OH / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.4 Å
AuthorsBuehrmann, M. / Mueller, M.P. / Wiedemann, B. / 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)41,6762
Polymers41,3431
Non-polymers3321
Water79344
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area17030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.050, 74.770, 78.410
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-8OH / 2-phenyl-~{N}4-(thiophen-2-ylmethyl)quinazoline-4,7-diamine


Mass: 332.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16N4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 2.34 Å3/Da / Density % sol: 47.33 %
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: X10SA / Wavelength: 0.9205 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9205 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 15944 / % possible obs: 99.9 % / Redundancy: 6.5 % / Rrim(I) all: 0.083 / Net I/σ(I): 17.36
Reflection shellResolution: 2.4→2.5 Å / Redundancy: 6.8 % / Mean I/σ(I) obs: 1.92 / Rrim(I) all: 1.153 / % 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: 2.4→42.109 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 26.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2407 798 5.01 %RANDOM
Rwork0.2043 ---
obs0.2062 15944 99.94 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→42.109 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2662 0 24 44 2730
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032749
X-RAY DIFFRACTIONf_angle_d0.6383732
X-RAY DIFFRACTIONf_dihedral_angle_d11.3861648
X-RAY DIFFRACTIONf_chiral_restr0.042419
X-RAY DIFFRACTIONf_plane_restr0.003474
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4001-2.55040.32521300.28332465X-RAY DIFFRACTION100
2.5504-2.74730.3271300.26672464X-RAY DIFFRACTION100
2.7473-3.02370.28091320.24212519X-RAY DIFFRACTION100
3.0237-3.46110.2831320.22842498X-RAY DIFFRACTION100
3.4611-4.35980.19651340.18452544X-RAY DIFFRACTION100
4.3598-42.11560.22281400.17912656X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -6.6815 Å / Origin y: -3.5839 Å / Origin z: 15.7565 Å
111213212223313233
T0.4165 Å20.0365 Å2-0.0648 Å2-0.3128 Å2-0.0378 Å2--0.2748 Å2
L3.4637 °20.2781 °2-0.5375 °2-1.6265 °20.1256 °2--1.2381 °2
S0.0585 Å °-0.2328 Å °0.0463 Å °0.127 Å °-0.0672 Å °-0.0632 Å °-0.0313 Å °0.0521 Å °0.0016 Å °
Refinement TLS groupSelection details: (chain A and resseq 5:354)

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