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- PDB-5ke0: Discovery of 1-1H-Pyrazolo 4,3-c pyridine-6-yl urea Inhibitors of... -

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Basic information

Entry
Database: PDB / ID: 5ke0
TitleDiscovery of 1-1H-Pyrazolo 4,3-c pyridine-6-yl urea Inhibitors of Extracellular Signal Regulated Kinase ERK for the Treatment of Cancers
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / MAP KINASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / RHO GTPases Activate WASPs and WAVEs / IFNG signaling activates MAPKs ...phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / RHO GTPases Activate WASPs and WAVEs / IFNG signaling activates MAPKs / Transcriptional and post-translational regulation of MITF-M expression and activity / Negative feedback regulation of MAPK pathway / Gastrin-CREB signalling pathway via PKC and MAPK / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of actin dynamics for phagocytic cup formation / Estrogen-stimulated signaling through PRKCZ / Growth hormone receptor signaling / Spry regulation of FGF signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Oxidative Stress Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Oncogene Induced Senescence / Signaling by Activin / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Signal attenuation / NCAM signaling for neurite out-growth / Negative regulation of FGFR1 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / Regulation of the apoptosome activity / Signal transduction by L1 / Negative regulation of FGFR2 signaling / RHO GTPases Activate NADPH Oxidases / Negative regulation of MAPK pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interferon gamma signaling / FCERI mediated MAPK activation / Regulation of HSF1-mediated heat shock response / MAP2K and MAPK activation / diadenosine tetraphosphate biosynthetic process / Recycling pathway of L1 / neural crest cell development / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / response to epidermal growth factor / mitogen-activated protein kinase kinase kinase binding / positive regulation of macrophage proliferation / outer ear morphogenesis / regulation of cellular pH / Thrombin signalling through proteinase activated receptors (PARs) / regulation of Golgi inheritance / RAF/MAP kinase cascade / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / Neutrophil degranulation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / : / positive regulation of macrophage chemotaxis / ERBB2-ERBB3 signaling pathway / lung morphogenesis / response to exogenous dsRNA / regulation of cytoskeleton organization / face development / progesterone receptor signaling pathway / androgen receptor signaling pathway / pseudopodium / positive regulation of telomere capping / Bergmann glial cell differentiation / thyroid gland development / negative regulation of cell differentiation / decidualization / steroid hormone receptor signaling pathway / MAP kinase activity / regulation of ossification / mitogen-activated protein kinase / phosphatase binding / Schwann cell development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / sensory perception of pain / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / ERK1 and ERK2 cascade / myelination / dendrite cytoplasm / phosphotyrosine residue binding / cellular response to amino acid starvation / RNA polymerase II CTD heptapeptide repeat kinase activity / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / caveola / positive regulation of translation / long-term synaptic potentiation
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / : / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / : / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-6S9 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.68 Å
AuthorsHruza, A. / Lim, J.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of 1-(1H-Pyrazolo[4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers.
Authors: Lim, J. / Kelley, E.H. / Methot, J.L. / Zhou, H. / Petrocchi, A. / Chen, H. / Hill, S.E. / Hinton, M.C. / Hruza, A. / Jung, J.O. / Maclean, J.K. / Mansueto, M. / Naumov, G.N. / Philippar, U. ...Authors: Lim, J. / Kelley, E.H. / Methot, J.L. / Zhou, H. / Petrocchi, A. / Chen, H. / Hill, S.E. / Hinton, M.C. / Hruza, A. / Jung, J.O. / Maclean, J.K. / Mansueto, M. / Naumov, G.N. / Philippar, U. / Raut, S. / Spacciapoli, P. / Sun, D. / Siliphaivanh, P.
History
DepositionJun 9, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2016Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations / Refinement description
Category: citation / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Mar 6, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
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 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2007
Polymers42,3621
Non-polymers8396
Water4,846269
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area940 Å2
ΔGint-68 kcal/mol
Surface area16000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.105, 91.334, 62.917
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Mitogen-activated protein kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK ...MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAPK 2


Mass: 42361.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Mapk1, Erk2, Mapk, Prkm1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P63086, mitogen-activated protein kinase
#2: Chemical ChemComp-6S9 / 1-[3-(2-methylpyridin-4-yl)-1~{H}-pyrazolo[4,3-c]pyridin-6-yl]-3-(phenylmethyl)urea


Mass: 358.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18N6O
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 269 / 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: 2.59 Å3/Da / Density % sol: 52.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 0.1M MES, PH 6.4, 2.0M AMMONIUM SULFATE, 5% PEG 400, 0.5% DMSO, 1% GLYEROL, 0.0005M OLOMOUCINE. 10 DAY SOAK WITH NEW COMPOUND AT 500 MICROMOLAR CONCENTRATION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 22, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.68→62.92 Å / Num. obs: 47325 / % possible obs: 99.8 % / Redundancy: 6.3 % / Biso Wilson estimate: 24.37 Å2 / Rmerge(I) obs: 0.067 / Rsym value: 0.067 / Net I/σ(I): 16.7
Reflection shellResolution: 1.681→1.686 Å / Redundancy: 6.7 % / Rmerge(I) obs: 0.635 / Mean I/σ(I) obs: 2.6 / % possible all: 100

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Processing

Software
NameVersionClassification
XDS(VERSION December 6 2010)data reduction
SCALAdata scaling
MOLREPphasing
BUSTER2.11.6refinement
RefinementResolution: 1.68→16.93 Å / Cor.coef. Fo:Fc: 0.9552 / Cor.coef. Fo:Fc free: 0.9507 / SU R Cruickshank DPI: 0.103 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.088 / SU Rfree Blow DPI: 0.084 / SU Rfree Cruickshank DPI: 0.082
RfactorNum. reflection% reflectionSelection details
Rfree0.1905 2367 5.01 %RANDOM
Rwork0.1678 ---
obs0.1689 47210 99.64 %-
Displacement parametersBiso mean: 29.68 Å2
Baniso -1Baniso -2Baniso -3
1--2.7057 Å20 Å20 Å2
2--0.35 Å20 Å2
3---2.3557 Å2
Refine analyzeLuzzati coordinate error obs: 0.188 Å
Refinement stepCycle: LAST / Resolution: 1.68→16.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2799 0 52 269 3120
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015744HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0110382HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1267SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes74HARMONIC2
X-RAY DIFFRACTIONt_gen_planes864HARMONIC5
X-RAY DIFFRACTIONt_it5744HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.66
X-RAY DIFFRACTIONt_other_torsion14.21
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion370SEMIHARMONIC5
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_contact6479SEMIHARMONIC4
LS refinement shellResolution: 1.68→1.72 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2049 166 4.85 %
Rwork0.1867 3258 -
all0.1876 3424 -
obs--98.66 %
Refinement TLS params.Method: refined / Origin x: 53.1969 Å / Origin y: 19.5008 Å / Origin z: 19.38 Å
111213212223313233
T-0.0231 Å20.0015 Å2-0.003 Å2--0.0631 Å20.0029 Å2---0.0789 Å2
L0.8927 °2-0.3153 °2-0.5239 °2-0.6669 °20.0418 °2--1.0382 °2
S0.0221 Å °0.0827 Å °-0.0667 Å °-0.0378 Å °-0.046 Å °0.0735 Å °-0.0195 Å °-0.0364 Å °0.0239 Å °
Refinement TLS groupSelection details: { A|* }

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