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- PDB-3ocg: P38 Alpha kinase complexed with a 5-amino-pyrazole based inhibitor -

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Basic information

Entry
Database: PDB / ID: 3ocg
TitleP38 Alpha kinase complexed with a 5-amino-pyrazole based inhibitor
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / P38 map kinase / serine/threonine-protein kinase / transferase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


stress-activated protein kinase signaling cascade / 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 / cartilage condensation ...stress-activated protein kinase signaling cascade / 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 / cartilage condensation / positive regulation of myoblast fusion / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of muscle cell differentiation / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / D-glucose import / regulation of cytokine production involved in inflammatory response / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / p38MAPK cascade / 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 / MAP kinase activity / RHO GTPases Activate NADPH Oxidases / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / mitogen-activated protein kinase / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / 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 / positive regulation of D-glucose import / stem cell differentiation / activated TAK1 mediates p38 MAPK activation / cellular response to ionizing radiation / negative regulation of inflammatory response to antigenic stimulus / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / placenta development / NOD1/2 Signaling Pathway / cellular response to virus / platelet activation / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / glucose metabolic process / ADP signalling through P2Y purinoceptor 1 / chemotaxis / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / peptidyl-serine phosphorylation / cellular response to lipopolysaccharide / 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 / Neutrophil degranulation / positive regulation of gene expression / regulation of transcription by RNA polymerase II / apoptotic process / 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 ...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-OCG / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / molecular replacement / Resolution: 2.21 Å
AuthorsSack, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: 5-Amino-pyrazoles as potent and selective p38α inhibitors
Authors: Das, J. / Moquin, R.V. / Dyckman, A.J. / Li, T. / Pitt, S. / Zhang, R. / Shen, D.R. / McIntyre, K.W. / Gillooly, K. / Doweyko, A.M. / Newitt, J.A. / Sack, J.S. / Zhang, H. / Kiefer, S.E. / ...Authors: Das, J. / Moquin, R.V. / Dyckman, A.J. / Li, T. / Pitt, S. / Zhang, R. / Shen, D.R. / McIntyre, K.W. / Gillooly, K. / Doweyko, A.M. / Newitt, J.A. / Sack, J.S. / Zhang, H. / Kiefer, S.E. / Kish, K. / McKinnon, M. / Barrish, J.C. / Dodd, J.H. / Schieven, G.L. / Leftheris, K.
History
DepositionAug 10, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 17, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 2, 2020Group: Database references / Derived calculations / Structure summary
Category: struct_keywords / struct_ref_seq_dif / struct_site
Item: _struct_keywords.text / _struct_ref_seq_dif.details ..._struct_keywords.text / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 21, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)42,5072
Polymers42,1051
Non-polymers4021
Water2,324129
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.940, 71.430, 80.550
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 / 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: 42105.004 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSBP, CSBP1, CSBP2, CSPB1, MAPK14, MXI2 / Cell line (production host): BL21(DE3) / Production host: Escherichia coli (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-OCG / 5-amino-N-[5-(isoxazol-3-ylcarbamoyl)-2-methylphenyl]-1-phenyl-1H-pyrazole-4-carboxamide


Mass: 402.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18N6O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 129 / 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: 47.01 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 14, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 17075 / % possible obs: 84.1 % / Observed criterion σ(I): 0 / Redundancy: 5.9 % / Biso Wilson estimate: 46.39 Å2 / Rmerge(I) obs: 0.062 / Net I/σ(I): 30
Reflection shellResolution: 2.28→2.37 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.298 / Mean I/σ(I) obs: 3.3 / % possible all: 59.8

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Processing

Software
NameVersionClassification
AMoREphasing
BUSTER2.9.4refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: molecular replacement / Resolution: 2.21→29.43 Å / Cor.coef. Fo:Fc: 0.9185 / Cor.coef. Fo:Fc free: 0.8858 / SU R Cruickshank DPI: 0.356 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.27 629 3.69 %RANDOM
Rwork0.2118 ---
obs0.214 17044 84.21 %-
Displacement parametersBiso mean: 50.19 Å2
Baniso -1Baniso -2Baniso -3
1-12.0856 Å20 Å20 Å2
2--7.2689 Å20 Å2
3----19.3544 Å2
Refine analyzeLuzzati coordinate error obs: 0.327 Å
Refinement stepCycle: LAST / Resolution: 2.21→29.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2716 0 30 129 2875
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.0128122
X-RAY DIFFRACTIONt_angle_deg1.1738182
X-RAY DIFFRACTIONt_dihedral_angle_d9702
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes702
X-RAY DIFFRACTIONt_gen_planes4015
X-RAY DIFFRACTIONt_it281220
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.96
X-RAY DIFFRACTIONt_other_torsion21.4
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion3615
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact32584
LS refinement shellResolution: 2.21→2.34 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.3453 42 2.6 %
Rwork0.2505 1576 -
all0.253 1618 -
obs--84.21 %

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