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- PDB-3hrb: p38 kinase Crystal structure in complex with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 3hrb
Titlep38 kinase Crystal structure in complex with small molecule inhibitor
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / p38 MAP KINASE / INHIBITOR COMPLEX / Alternative splicing / ATP-binding / Cytoplasm / Kinase / Nucleotide-binding / Nucleus / Phosphoprotein / Polymorphism / Serine/threonine-protein kinase
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 / cartilage condensation ...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 / cartilage condensation / DSCAM interactions / 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 / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / glucose import / 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 / signal transduction in response to DNA damage / positive regulation of myoblast differentiation / 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 interleukin-12 production / positive regulation of brown fat cell differentiation / 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 / NOD1/2 Signaling Pathway / bone development / placenta development / response to insulin / 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 / ADP signalling through P2Y purinoceptor 1 / osteoblast differentiation / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / chemotaxis / cellular senescence / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / peptidyl-serine phosphorylation / 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 / 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-I39 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
AuthorsSegarra, V. / Lumeras, W. / Vidal, B. / Leonard, P. / Fisher, M. / Lamers, M.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Design, synthesis, and structure-activity relationships of aminopyridine N-oxides, a novel scaffold for the potent and selective inhibition of p38 mitogen activated protein kinase
Authors: Lumeras, W. / Caturla, F. / Vidal, L. / Esteve, C. / Balague, C. / Orellana, A. / Dominguez, M. / Roca, R. / Huerta, J.M. / Godessart, N. / Vidal, B.
History
DepositionJun 9, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Sep 1, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)41,5522
Polymers41,2121
Non-polymers3401
Water3,243180
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.220, 86.750, 122.230
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 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha / Cytokine suppressive anti- ...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: 41212.000 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Description: The plasmid used is annotated as Sareum proprietary
Gene: MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-I39 / [3-amino-2-(2-methylphenyl)-1-oxidopyridin-4-yl](2,4-difluorophenyl)methanone


Mass: 340.323 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H14F2N2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 2.91 Å3/Da / Density % sol: 57.73 % / Mosaicity: 0.54 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 22% PEG 3350, 0.2M NaCl, 0.1M Bis-Tris pH 6.5, 1mM THP, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Jun 23, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→70.744 Å / Num. all: 40419 / Num. obs: 20806 / % possible obs: 84.2 % / Redundancy: 1.9 % / Biso Wilson estimate: 35.9 Å2 / Rmerge(I) obs: 0.057 / Rsym value: 0.057 / Net I/σ(I): 9.5
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.367 / Mean I/σ(I) obs: 2.2 / Num. unique all: 5586 / Rsym value: 0.367 / % possible all: 89.1

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.5 Å29.7 Å
Translation3.5 Å29.7 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.9data scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1A9U

1a9u


Resolution: 2.2→29.7 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.812 / SU B: 6.386 / SU ML: 0.158 / SU R Cruickshank DPI: 0.315 / SU Rfree: 0.241 / Cross valid method: THROUGHOUT / ESU R: 0.315 / ESU R Free: 0.241
RfactorNum. reflection% reflectionSelection details
Rfree0.26 1072 5.2 %RANDOM
Rwork0.214 ---
obs0.217 19725 82.58 %-
all-40419 --
Displacement parametersBiso max: 65.17 Å2 / Biso mean: 26.83 Å2 / Biso min: 10.45 Å2
Baniso -1Baniso -2Baniso -3
1--0.44 Å20 Å20 Å2
2---0.77 Å20 Å2
3---1.2 Å2
Refinement stepCycle: LAST / Resolution: 2.2→29.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2766 0 25 180 2971
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONp_bond_d0.010.022
X-RAY DIFFRACTIONp_angle_d1.2021.972
X-RAY DIFFRACTIONp_angle_deg
X-RAY DIFFRACTIONp_planar_d
X-RAY DIFFRACTIONp_hb_or_metal_coord
X-RAY DIFFRACTIONp_mcbond_it0.7181.5
X-RAY DIFFRACTIONp_mcangle_it1.3332
X-RAY DIFFRACTIONp_scbond_it1.4413
X-RAY DIFFRACTIONp_scangle_it2.4024.5
X-RAY DIFFRACTIONp_plane_restr0.0050.021
X-RAY DIFFRACTIONp_chiral_restr0.0710.2
X-RAY DIFFRACTIONp_singtor_nbd
X-RAY DIFFRACTIONp_multtor_nbd
X-RAY DIFFRACTIONp_xhyhbond_nbd
X-RAY DIFFRACTIONp_xyhbond_nbd
X-RAY DIFFRACTIONp_planar_tor
X-RAY DIFFRACTIONp_staggered_tor
X-RAY DIFFRACTIONp_orthonormal_tor
X-RAY DIFFRACTIONp_transverse_tor
X-RAY DIFFRACTIONp_special_tor

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