[English] 日本語
Yorodumi
- PDB-5ke0: Discovery of 1-1H-Pyrazolo 4,3-c pyridine-6-yl urea Inhibitors of... -

+
Open data


ID or keywords:

Loading...

-
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 / Transcriptional and post-translational regulation of MITF-M expression and activity / Negative feedback regulation of MAPK pathway ...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 / 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 / IFNG signaling activates MAPKs / Golgi Cisternae Pericentriolar Stack Reorganization / RHO GTPases Activate WASPs and WAVEs / 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 / Regulation of actin dynamics for phagocytic cup formation / 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 / Signaling by Activin / Negative regulation of FGFR2 signaling / Signal transduction by L1 / 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 / diadenosine tetraphosphate biosynthetic process / MAP2K and MAPK activation / neural crest cell development / Recycling pathway of L1 / cellular response to toxic substance / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / mitogen-activated protein kinase kinase kinase binding / cellular response to methionine / response to epidermal growth factor / positive regulation of macrophage proliferation / response to alcohol / regulation of cellular pH / outer ear morphogenesis / regulation of Golgi inheritance / labyrinthine layer blood vessel development / RAF/MAP kinase cascade / Thrombin signalling through proteinase activated receptors (PARs) / ERBB signaling pathway / Neutrophil degranulation / mammary gland epithelial cell proliferation / trachea formation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / cellular response to insulin-like growth factor stimulus / ERBB2-ERBB3 signaling pathway / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / response to exogenous dsRNA / face development / positive regulation of telomere maintenance / lung morphogenesis / response to testosterone / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / decidualization / negative regulation of cell differentiation / MAP kinase activity / regulation of ossification / JUN kinase activity / mitogen-activated protein kinase / phosphatase binding / Schwann cell development / progesterone receptor signaling pathway / stress-activated MAPK cascade / estrous cycle / positive regulation of cardiac muscle cell proliferation / cellular response to platelet-derived growth factor stimulus / cellular response to cAMP / sensory perception of pain / dendrite cytoplasm / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / ERK1 and ERK2 cascade / cellular response to epidermal growth factor stimulus
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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|* }

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more