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- PDB-3mpt: Crystal structure of P38 kinase in complex with a pyrrole-2-carbo... -

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Basic information

Entry
Database: PDB / ID: 3mpt
TitleCrystal structure of P38 kinase in complex with a pyrrole-2-carboxamide inhibitor
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / P38 / SERINE/THREONINE PROTEIN KINASE / MAP KINASE / Pyrrole-2-Carboxamides / inhibitor / TRANSFERASE-TRANSFERASE INHIBIATOR complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / positive regulation of myoblast fusion / cartilage condensation / stress-activated protein kinase signaling cascade / 3'-UTR-mediated mRNA stabilization / CD163 mediating an anti-inflammatory response / positive regulation of cyclase activity / response to dietary excess ...Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of synaptic membrane adhesion / stress-induced premature senescence / positive regulation of myoblast fusion / cartilage condensation / stress-activated protein kinase signaling cascade / 3'-UTR-mediated mRNA stabilization / CD163 mediating an anti-inflammatory response / positive regulation of cyclase activity / response to dietary excess / positive regulation of myotube differentiation / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of muscle cell differentiation / cellular response to UV-B / mitogen-activated protein kinase p38 binding / Myogenesis / Platelet sensitization by LDL / NFAT protein binding / cellular response to lipoteichoic acid / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / p38MAPK cascade / ERK/MAPK targets / MAP kinase kinase activity / Regulation of MITF-M-dependent genes involved in pigmentation / cellular response to vascular endothelial growth factor stimulus / MAP kinase activity / mitogen-activated protein kinase / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / RHO GTPases Activate NADPH Oxidases / negative regulation of hippo signaling / positive regulation of myoblast differentiation / osteoclast differentiation / positive regulation of interleukin-12 production / signal transduction in response to DNA damage / p38MAPK events / positive regulation of erythrocyte differentiation / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / cellular response to virus / activated TAK1 mediates p38 MAPK activation / negative regulation of inflammatory response to antigenic stimulus / negative regulation of canonical Wnt signaling pathway / platelet activation / bone development / response to insulin / NOD1/2 Signaling Pathway / cellular senescence / VEGFA-VEGFR2 Pathway / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / chemotaxis / spindle pole / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / MAPK cascade / ADP signalling through P2Y purinoceptor 1 / cellular response to lipopolysaccharide / secretory granule lumen / protein phosphatase binding / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / cell surface receptor signaling pathway / nuclear speck / intracellular signal transduction / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / positive regulation of gene expression / regulation of transcription by RNA polymerase II / Neutrophil degranulation / glutamatergic synapse / enzyme binding / signal transduction / mitochondrion / DNA-templated transcription / extracellular region / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
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-1GK / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.89 Å
AuthorsSomers, D.O.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: The discovery and initial optimisation of pyrrole-2-carboxamides as inhibitors of p38alpha MAP kinase.
Authors: Down, K. / Bamborough, P. / Alder, C. / Campbell, A. / Christopher, J.A. / Gerelle, M. / Ludbrook, S. / Mallett, D. / Mellor, G. / Miller, D.D. / Pearson, R. / Ray, K. / Solanke, Y. / Somers, D.
History
DepositionApr 27, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 7, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)43,2355
Polymers42,6511
Non-polymers5854
Water5,693316
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.376, 85.859, 124.463
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Mitogen-activated protein kinase 14 / MAP kinase 14 / MAPK 14 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / ...MAP kinase 14 / MAPK 14 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti-inflammatory drug-binding protein / CSAID-binding protein / CSBP / MAX-interacting protein 2 / MAP kinase MXI2 / SAPK2A


Mass: 42650.738 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 / Plasmid: pRSETA / Production host: Escherichia coli (E. coli) / Strain (production host): BRL
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-1GK / N-(furan-2-ylmethyl)-4-[(2-methylphenyl)carbonyl]-1H-pyrrole-2-carboxamide


Mass: 308.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16N2O3
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 316 / 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: 2.84 Å3/Da / Density % sol: 56.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: See publication for details , pH 6.5, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Oct 20, 2005 / Details: mirrors
RadiationMonochromator: Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.89→62.23 Å / Num. obs: 37532 / % possible obs: 93.8 % / Redundancy: 5.66 % / Biso Wilson estimate: 18.1 Å2 / Rmerge(I) obs: 0.138 / Χ2: 1 / Net I/σ(I): 7.9 / Scaling rejects: 1608
Reflection shellResolution: 1.89→1.95 Å / Redundancy: 5.53 % / Rmerge(I) obs: 0.446 / Mean I/σ(I) obs: 3.5 / Num. measured all: 19775 / Num. unique all: 3573 / Χ2: 0.99 / % possible all: 90.8

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Processing

Software
NameVersionClassificationNB
d*TREKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
MAR345dtbdata collection
d*TREKdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1wfc

1wfc


Resolution: 1.89→20 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.908 / WRfactor Rfree: 0.279 / WRfactor Rwork: 0.217 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.752 / SU B: 5.871 / SU ML: 0.155 / SU R Cruickshank DPI: 0.169 / SU Rfree: 0.171 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.171 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.298 1869 5 %RANDOM
Rwork0.236 ---
obs0.239 37456 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 77.24 Å2 / Biso mean: 31.085 Å2 / Biso min: 6.03 Å2
Baniso -1Baniso -2Baniso -3
1--0.51 Å20 Å20 Å2
2---0.35 Å20 Å2
3---0.87 Å2
Refinement stepCycle: LAST / Resolution: 1.89→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2801 0 41 316 3158
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222917
X-RAY DIFFRACTIONr_angle_refined_deg1.5111.9753959
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4335349
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.25224.088137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.03815501
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4111518
X-RAY DIFFRACTIONr_chiral_restr0.0970.2440
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212237
X-RAY DIFFRACTIONr_mcbond_it1.18321741
X-RAY DIFFRACTIONr_mcangle_it2.16632828
X-RAY DIFFRACTIONr_scbond_it3.1184.51176
X-RAY DIFFRACTIONr_scangle_it4.55261129
LS refinement shellResolution: 1.89→1.939 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.497 125 -
Rwork0.433 2603 -
all-2728 -
obs--100 %

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