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- PDB-5o8v: Covalent Inhibitor 4a bound to the Lipid Pocket of p38alpha Mutan... -

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Basic information

Entry
Database: PDB / ID: 5o8v
TitleCovalent Inhibitor 4a bound to the Lipid Pocket of p38alpha Mutant S251C
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / kinase / small molecule / lipid pocket / p38 / covalent / mutant
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 / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA ...stress-activated protein kinase signaling cascade / positive regulation of cyclase activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / CD163 mediating an anti-inflammatory response / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / positive regulation of myoblast fusion / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / cellular response to UV-B / positive regulation of muscle cell differentiation / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / Myogenesis / positive regulation of myotube differentiation / NFAT protein binding / regulation of cytokine production involved in inflammatory response / D-glucose import / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / 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 / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / JUN kinase activity / mitogen-activated protein kinase / chondrocyte differentiation / negative regulation of hippo signaling / positive regulation of myoblast differentiation / vascular endothelial growth factor receptor signaling pathway / skeletal muscle tissue development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / 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 / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / positive regulation of D-glucose import / activated TAK1 mediates p38 MAPK activation / stem cell differentiation / response to insulin / placenta development / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / NOD1/2 Signaling Pathway / cell morphogenesis / bone development / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / positive regulation of protein import into nucleus / glucose metabolic process / spindle pole / chemotaxis / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / cellular senescence / ADP signalling through P2Y purinoceptor 1 / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / protein phosphatase binding / secretory granule lumen / Oxidative Stress Induced Senescence / angiogenesis / 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
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-9O2 / 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
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)41,7712
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 area16040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.200, 74.250, 77.820
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: 41359.258 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-9O2 / ~{N}-[3-[7-azanyl-4-(2-phenylethylamino)quinazolin-2-yl]phenyl]propanamide


Mass: 411.499 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.28 Å3/Da / Density % sol: 46.03 %
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: 24856 / % possible obs: 100 % / Redundancy: 13.21 % / Rpim(I) all: 0.094 / Net I/σ(I): 21.36
Reflection shellResolution: 2→2.05 Å / Redundancy: 13.71 % / Mean I/σ(I) obs: 2.78 / Rpim(I) all: 1.049 / % possible all: 100

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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→48.99 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.92 / SU B: 5.394 / SU ML: 0.146 / Cross valid method: THROUGHOUT / ESU R: 0.184 / ESU R Free: 0.181 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26906 1309 5 %RANDOM
Rwork0.20598 ---
obs0.20909 24856 99.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.332 Å2
Baniso -1Baniso -2Baniso -3
1-0.35 Å2-0 Å2-0 Å2
2---1.55 Å20 Å2
3---1.2 Å2
Refinement stepCycle: 1 / Resolution: 2→48.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2598 0 31 79 2708
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0192692
X-RAY DIFFRACTIONr_bond_other_d0.0030.022557
X-RAY DIFFRACTIONr_angle_refined_deg1.781.9783661
X-RAY DIFFRACTIONr_angle_other_deg1.1093.0045862
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1035324
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.06624.202119
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.52515444
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.4371514
X-RAY DIFFRACTIONr_chiral_restr0.10.2416
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213001
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02613
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_it4.0534.2731308
X-RAY DIFFRACTIONr_mcbond_other4.0554.271307
X-RAY DIFFRACTIONr_mcangle_it5.6256.3771628
X-RAY DIFFRACTIONr_mcangle_other5.6236.381629
X-RAY DIFFRACTIONr_scbond_it4.2214.4871384
X-RAY DIFFRACTIONr_scbond_other4.2194.4891385
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.1946.6212034
X-RAY DIFFRACTIONr_long_range_B_refined8.98639.51611483
X-RAY DIFFRACTIONr_long_range_B_other8.98339.52511444
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
Rfree0.357 95 -
Rwork0.31 1793 -
obs--99.95 %

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