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Basic information

Entry
Database: PDB / ID: 6m95
TitleStructure-based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridine-2-one based p38 MAP Kinase Inhibitors by scaffold hopping: compound 1
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE / p38 MAP Kinase inhibitors / sbdd
Function / homology
Function and homology information


positive regulation of cyclase activity / 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 ...positive regulation of cyclase activity / 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 / stress-activated protein kinase signaling cascade / 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 / response to dietary excess / 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 muramyl dipeptide / RHO GTPases Activate NADPH Oxidases / regulation of ossification / MAP kinase activity / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / signal transduction in response to DNA damage / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / 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 / positive regulation of erythrocyte differentiation / placenta development / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / negative regulation of canonical Wnt signaling pathway / response to insulin / NOD1/2 Signaling Pathway / bone development / cell morphogenesis / platelet activation / osteoblast differentiation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / 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 / protein phosphatase binding / angiogenesis / peptidyl-serine phosphorylation / secretory granule lumen / Oxidative Stress Induced Senescence / cellular response to lipopolysaccharide / 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. / 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
Similarity search - Domain/homology
Chem-J8S / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsLane, W. / Okada, K.
CitationJournal: Chemmedchem / Year: 2019
Title: Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 1.
Authors: Kaieda, A. / Takahashi, M. / Fukuda, H. / Okamoto, R. / Morimoto, S. / Gotoh, M. / Miyazaki, T. / Hori, Y. / Unno, S. / Kawamoto, T. / Tanaka, T. / Itono, S. / Takagi, T. / Sugimoto, H. / ...Authors: Kaieda, A. / Takahashi, M. / Fukuda, H. / Okamoto, R. / Morimoto, S. / Gotoh, M. / Miyazaki, T. / Hori, Y. / Unno, S. / Kawamoto, T. / Tanaka, T. / Itono, S. / Takagi, T. / Sugimoto, H. / Okada, K. / Snell, G. / Bertsch, R. / Nguyen, J. / Sang, B.C. / Miwatashi, S.
History
DepositionAug 22, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2019Provider: repository / Type: Initial release
Revision 1.1May 29, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)45,0442
Polymers44,6891
Non-polymers3551
Water5,585310
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)68.523, 70.124, 74.599
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: 44688.680 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: unidentified baculovirus
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-J8S / (4-benzylpiperidin-1-yl)[2-methoxy-4-(methylsulfanyl)phenyl]methanone


Mass: 355.494 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C21H25NO2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 310 / 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: 2.01 Å3/Da / Density % sol: 38.66 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 7.4 / Details: 16.% PEG 3350, 0.06M MES, 0.04M MES_Na

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Sep 1, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→49.01 Å / Num. obs: 33573 / % possible obs: 98.75 % / Redundancy: 4.5 % / Biso Wilson estimate: 19.14 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.06831 / Rpim(I) all: 0.03589 / Net I/σ(I): 15.58
Reflection shellResolution: 1.8→1.864 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.4724 / Mean I/σ(I) obs: 2.61 / Num. unique obs: 3218 / CC1/2: 0.803 / Rpim(I) all: 0.2669 / % possible all: 96.03

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→49.01 Å / SU ML: 0.1949 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.8558
RfactorNum. reflection% reflection
Rfree0.2084 1705 5.08 %
Rwork0.1724 --
obs0.1743 33571 98.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 22.72 Å2
Refinement stepCycle: LAST / Resolution: 1.8→49.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2683 0 25 310 3018
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01542772
X-RAY DIFFRACTIONf_angle_d1.46463763
X-RAY DIFFRACTIONf_chiral_restr0.0962420
X-RAY DIFFRACTIONf_plane_restr0.0091485
X-RAY DIFFRACTIONf_dihedral_angle_d9.22931667
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.25721580.23442512X-RAY DIFFRACTION95.7
1.85-1.910.25931510.19932580X-RAY DIFFRACTION97.82
1.91-1.980.23711230.18472620X-RAY DIFFRACTION98.63
1.98-2.060.24221380.17732629X-RAY DIFFRACTION98.4
2.06-2.150.20771290.16082617X-RAY DIFFRACTION98.74
2.15-2.270.1971260.15772655X-RAY DIFFRACTION98.69
2.27-2.410.23581560.1682633X-RAY DIFFRACTION99.08
2.41-2.60.18691450.16732662X-RAY DIFFRACTION99.29
2.6-2.860.20611450.17072664X-RAY DIFFRACTION99.54
2.86-3.270.20591520.17512691X-RAY DIFFRACTION99.44
3.27-4.120.19011340.15892748X-RAY DIFFRACTION99.72
4.12-49.030.19821480.17852855X-RAY DIFFRACTION99.83
Refinement TLS params.Method: refined / Origin x: -11.6793450031 Å / Origin y: 4.83017000183 Å / Origin z: -18.4613198955 Å
111213212223313233
T0.0890714543402 Å2-0.00312144212595 Å2-0.00368707090706 Å2-0.0762210112619 Å2-0.00893327749868 Å2--0.0833584106562 Å2
L0.185569734165 °2-0.137824024132 °2-0.0650534625005 °2-0.457966031543 °20.0284088934799 °2--0.442691736804 °2
S0.021277791912 Å °0.00563959485048 Å °-0.0290957092217 Å °-0.000350236396769 Å °-0.0155238150268 Å °0.0329365977301 Å °0.0128299908575 Å °-0.0104396594882 Å °-5.83555561956E-5 Å °
Refinement TLS groupSelection details: all

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