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- PDB-2yix: Triazolopyridine Inhibitors of p38 -

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Entry
Database: PDB / ID: 2yix
TitleTriazolopyridine Inhibitors of p38
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 14
KeywordsTRANSFERASE / PHOSPHORYLATION / 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-YIX / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.3 Å
AuthorsMillan, D.S. / Anderson, M. / Bunnage, M.E. / Burrows, J.L. / Butcher, K.J. / Dodd, P.G. / Evans, T.J. / Fairman, D.A. / Han, s. / Hughes, S.J. ...Millan, D.S. / Anderson, M. / Bunnage, M.E. / Burrows, J.L. / Butcher, K.J. / Dodd, P.G. / Evans, T.J. / Fairman, D.A. / Han, s. / Hughes, S.J. / Irving, S.L. / Kilty, I.C. / Lemaitre, A. / Lewthawaite, R.A. / Mahke, A. / Marr, E. / Mathias, J.P. / Philip, J. / Phillips, C. / Smith, R.T. / Stefaniak, M.H. / Yeadon, M.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease.
Authors: Millan, D.S. / Bunnage, M.E. / Burrows, J.L. / Butcher, K.J. / Dodd, P.G. / Evans, T.J. / Fairman, D.A. / Hughes, S.J. / Kilty, I.C. / Lemaitre, A. / Lewthwaite, R.A. / Mahnke, A. / Mathias, ...Authors: Millan, D.S. / Bunnage, M.E. / Burrows, J.L. / Butcher, K.J. / Dodd, P.G. / Evans, T.J. / Fairman, D.A. / Hughes, S.J. / Kilty, I.C. / Lemaitre, A. / Lewthwaite, R.A. / Mahnke, A. / Mathias, J.P. / Philip, J. / Smith, R.T. / Stefaniak, M.H. / Yeadon, M. / Phillips, C.
History
DepositionMay 17, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 30, 2011Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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)40,6332
Polymers40,2631
Non-polymers3691
Water4,918273
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.944, 86.523, 122.580
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 / P38 KINASE / MAP KINASE 14 / MAPK 14 / CYTOKINE SUPPRESSIVE ANTI-INFLAMMATORY DRUG-BINDING PROTEIN ...P38 KINASE / MAP KINASE 14 / MAPK 14 / CYTOKINE SUPPRESSIVE ANTI-INFLAMMATORY DRUG-BINDING PROTEIN / CSAID-BINDING PROTEIN / CSBP / MAP KINASE MXI2 / MAX-INTERACTING PROTEIN 2 / MITOGEN-ACTIVATED PROTEIN KINASE P38 ALPHA / MAP KINASE P38 ALPHA / SAPK2A


Mass: 40263.047 Da / Num. of mol.: 1 / Fragment: RESIDUES 4-354
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: Q16539, mitogen-activated protein kinase
#2: Chemical ChemComp-YIX / 1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea / CE-159167


Mass: 369.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23N5OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 273 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.03 Å3/Da / Density % sol: 59.35 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→25 Å / Num. obs: 21609 / % possible obs: 96 % / Observed criterion σ(I): 1 / Redundancy: 2.8 % / Biso Wilson estimate: 44.05 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 12

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Processing

SoftwareName: BUSTER / Version: 2.9.6 / Classification: refinement
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.3→24.75 Å / Cor.coef. Fo:Fc: 0.9332 / Cor.coef. Fo:Fc free: 0.9018 / SU R Cruickshank DPI: 0.264 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.295 / SU Rfree Blow DPI: 0.226 / SU Rfree Cruickshank DPI: 0.219
RfactorNum. reflection% reflectionSelection details
Rfree0.2472 1106 5.12 %RANDOM
Rwork0.1932 ---
obs0.1959 21609 96.4 %-
Displacement parametersBiso mean: 37.39 Å2
Baniso -1Baniso -2Baniso -3
1-4.8458 Å20 Å20 Å2
2--3.3912 Å20 Å2
3----8.237 Å2
Refine analyzeLuzzati coordinate error obs: 0.284 Å
Refinement stepCycle: LAST / Resolution: 2.3→24.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2834 0 26 273 3133
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012926HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.133974HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1012SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes81HARMONIC2
X-RAY DIFFRACTIONt_gen_planes421HARMONIC5
X-RAY DIFFRACTIONt_it2926HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion18.56
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion377SEMIHARMONIC5
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_contact3414SEMIHARMONIC4
LS refinement shellResolution: 2.3→2.41 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2899 144 5.39 %
Rwork0.245 2527 -
all0.2474 2671 -
obs--96.4 %

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