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- PDB-5o8u: Covalent Inhibitor 4b bound to the Lipid Pocket of p38alpha Mutan... -

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Basic information

Entry
Database: PDB / ID: 5o8u
TitleCovalent Inhibitor 4b bound to the Lipid Pocket of p38alpha Mutant S252C
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE / kinase / small molecule / lipid pocket / p38 / covalent / mutant
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. / 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-9O5 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsBuehrmann, M. / Rauh, D.
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2017
Title: Covalent Lipid Pocket Ligands Targeting p38 alpha MAPK Mutants.
Authors: Buhrmann, M. / Hardick, J. / Weisner, J. / Quambusch, L. / Rauh, D.
History
DepositionJun 14, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 6, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2May 2, 2018Group: Data collection / Category: reflns / reflns_shell
Item: _reflns.pdbx_Rpim_I_all / _reflns_shell.pdbx_Rpim_I_all
Revision 1.3Jan 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

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,7702
Polymers41,3591
Non-polymers4111
Water1,42379
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.580, 74.050, 76.710
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 / 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: 41359.258 Da / Num. of mol.: 1 / Mutation: yes
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-9O5 / 4-[3-[7-azanyl-4-(2-phenylethylamino)quinazolin-2-yl]phenyl]butan-2-one


Mass: 410.511 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H26N4O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.32 Å3/Da / Density % sol: 47.03 %
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: 1.00601 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00601 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 25307 / % possible obs: 100 % / Redundancy: 12.89 % / Rpim(I) all: 0.154 / Net I/σ(I): 14.42
Reflection shellResolution: 2→2.05 Å / Redundancy: 11.16 % / Mean I/σ(I) obs: 2.64 / Rpim(I) all: 0.908 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DLI

4dli


Resolution: 2→41.84 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.905 / SU B: 5.333 / SU ML: 0.142 / Cross valid method: THROUGHOUT / ESU R: 0.179 / ESU R Free: 0.169 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25236 1332 5 %RANDOM
Rwork0.20264 ---
obs0.20518 25307 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.502 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å2-0 Å2-0 Å2
2---1.44 Å20 Å2
3---1.29 Å2
Refinement stepCycle: 1 / Resolution: 2→41.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2615 0 31 79 2725
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192710
X-RAY DIFFRACTIONr_bond_other_d0.0040.022571
X-RAY DIFFRACTIONr_angle_refined_deg1.6991.9763688
X-RAY DIFFRACTIONr_angle_other_deg1.0713.0045897
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5735328
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.21724.37119
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.74815446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5151513
X-RAY DIFFRACTIONr_chiral_restr0.0980.2420
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213029
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02614
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.8633.3631321
X-RAY DIFFRACTIONr_mcbond_other2.863.3611320
X-RAY DIFFRACTIONr_mcangle_it4.1645.0241646
X-RAY DIFFRACTIONr_mcangle_other4.1635.0271647
X-RAY DIFFRACTIONr_scbond_it3.4553.5861389
X-RAY DIFFRACTIONr_scbond_other3.4543.5871390
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.175.2782043
X-RAY DIFFRACTIONr_long_range_B_refined7.52931.43611562
X-RAY DIFFRACTIONr_long_range_B_other7.51831.42711534
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 96 -
Rwork0.359 1833 -
obs--99.69 %

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