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- PDB-3nww: P38 Alpha kinase complexed with a 2-aminothiazol-5-yl-pyrimidine ... -

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Basic information

Entry
Database: PDB / ID: 3nww
TitleP38 Alpha kinase complexed with a 2-aminothiazol-5-yl-pyrimidine 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


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 / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / placenta development / cell morphogenesis / platelet activation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / chemotaxis / positive regulation of reactive oxygen species metabolic process / cellular senescence / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / peptidyl-serine phosphorylation / protein phosphatase binding / angiogenesis / Oxidative Stress Induced Senescence / secretory granule lumen / 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-3NW / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsSack, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38alpha MAP kinase inhibitors.
Authors: Lin, S. / Wrobleski, S.T. / Hynes, J. / Pitt, S. / Zhang, R. / Fan, Y. / Doweyko, A.M. / Kish, K.F. / Sack, J.S. / Malley, M.F. / Kiefer, S.E. / Newitt, J.A. / McKinnon, M. / Trzaskos, J. / ...Authors: Lin, S. / Wrobleski, S.T. / Hynes, J. / Pitt, S. / Zhang, R. / Fan, Y. / Doweyko, A.M. / Kish, K.F. / Sack, J.S. / Malley, M.F. / Kiefer, S.E. / Newitt, J.A. / McKinnon, M. / Trzaskos, J. / Barrish, J.C. / Dodd, J.H. / Schieven, G.L. / Leftheris, K.
History
DepositionJul 12, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 8, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jun 19, 2013Group: Database references
Revision 1.3Sep 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 1.4Feb 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)42,5882
Polymers42,1051
Non-polymers4831
Water3,765209
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.155, 75.055, 78.628
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-3NW / 1-[2-(2-{[2-(dimethylamino)ethyl]amino}-6-{2-[(1-methylethyl)amino]-1,3-thiazol-5-yl}pyrimidin-4-yl)benzyl]-3-ethylurea


Mass: 482.645 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H34N8OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 46.94 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Jul 20, 2005 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→78.64 Å / Num. obs: 24028 / % possible obs: 90 % / Observed criterion σ(I): 0 / Redundancy: 7.2 % / Biso Wilson estimate: 36.97 Å2 / Rmerge(I) obs: 0.059 / Net I/σ(I): 24.6
Reflection shellResolution: 2→2.11 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.473 / Mean I/σ(I) obs: 3.8 / % possible all: 57.5

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Processing

Software
NameVersionClassification
BUSTER2.9.3refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09→22.9 Å / Cor.coef. Fo:Fc: 0.9457 / Cor.coef. Fo:Fc free: 0.9311 / SU R Cruickshank DPI: 0.24 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2544 1158 5.16 %RANDOM
Rwork0.2115 ---
obs0.2137 22432 94.36 %-
Displacement parametersBiso mean: 40.46 Å2
Baniso -1Baniso -2Baniso -3
1--5.7777 Å20 Å20 Å2
2--7.1389 Å20 Å2
3----1.3612 Å2
Refine analyzeLuzzati coordinate error obs: 0.298 Å
Refinement stepCycle: LAST / Resolution: 2.09→22.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2741 0 34 209 2984
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.0128412
X-RAY DIFFRACTIONt_angle_deg1.0938552
X-RAY DIFFRACTIONt_dihedral_angle_d9792
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes692
X-RAY DIFFRACTIONt_gen_planes4045
X-RAY DIFFRACTIONt_it284120
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion19.34
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion3645
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_contact34534
LS refinement shellResolution: 2.09→2.19 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2436 116 4.83 %
Rwork0.2145 2287 -
all0.2158 2403 -
obs--94.36 %

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