[English] 日本語
Yorodumi
- PDB-2g01: Pyrazoloquinolones as Novel, Selective JNK1 inhibitors -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 2g01
TitlePyrazoloquinolones as Novel, Selective JNK1 inhibitors
Components
  • C-jun-amino-terminal kinase-interacting protein 1
  • Mitogen-activated protein kinase 8
KeywordsTRANSFERASE / JNK1 / c-jun N-Terminal Kinase / Protein Kinase JNK1 inhibitors
Function / homology
Function and homology information


dentate gyrus mossy fiber / regulation of CD8-positive, alpha-beta T cell proliferation / JUN phosphorylation / positive regulation of cell killing / Activation of BMF and translocation to mitochondria / Interleukin-38 signaling / basal dendrite / negative regulation of JUN kinase activity / positive regulation of establishment of protein localization to mitochondrion / Activation of BIM and translocation to mitochondria ...dentate gyrus mossy fiber / regulation of CD8-positive, alpha-beta T cell proliferation / JUN phosphorylation / positive regulation of cell killing / Activation of BMF and translocation to mitochondria / Interleukin-38 signaling / basal dendrite / negative regulation of JUN kinase activity / positive regulation of establishment of protein localization to mitochondrion / Activation of BIM and translocation to mitochondria / WNT5:FZD7-mediated leishmania damping / MAP-kinase scaffold activity / JUN kinase binding / positive regulation of cyclase activity / regulation of JNK cascade / mitogen-activated protein kinase kinase kinase binding / histone deacetylase regulator activity / mitogen-activated protein kinase kinase binding / NRAGE signals death through JNK / positive regulation of NLRP3 inflammasome complex assembly / protein kinase inhibitor activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / dendritic growth cone / positive regulation of protein metabolic process / JUN kinase activity / kinesin binding / peptidyl-threonine phosphorylation / mitogen-activated protein kinase / regulation of macroautophagy / response to mechanical stimulus / axonal growth cone / response to UV / stress-activated MAPK cascade / energy homeostasis / vesicle-mediated transport / negative regulation of protein binding / JNK cascade / cellular response to amino acid starvation / protein serine/threonine kinase binding / NRIF signals cell death from the nucleus / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / cellular response to reactive oxygen species / FCERI mediated MAPK activation / positive regulation of JNK cascade / regulation of circadian rhythm / mitochondrial membrane / cellular response to mechanical stimulus / histone deacetylase binding / peptidyl-serine phosphorylation / cellular senescence / rhythmic process / Signaling by ALK fusions and activated point mutants / MAPK cascade / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / regulation of protein localization / cellular response to lipopolysaccharide / cellular response to oxidative stress / protein phosphatase binding / Oxidative Stress Induced Senescence / response to oxidative stress / protein phosphorylation / positive regulation of apoptotic process / axon / protein serine kinase activity / neuronal cell body / protein serine/threonine kinase activity / synapse / positive regulation of gene expression / regulation of DNA-templated transcription / endoplasmic reticulum membrane / negative regulation of apoptotic process / perinuclear region of cytoplasm / enzyme binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
JIP1, SH3 domain / : / Mitogen-activated protein (MAP) kinase, JNK / Phosphotyrosine interaction domain (PTB/PID) / Phosphotyrosine interaction domain (PID) profile. / Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain / PTB/PI domain / Variant SH3 domain / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. ...JIP1, SH3 domain / : / Mitogen-activated protein (MAP) kinase, JNK / Phosphotyrosine interaction domain (PTB/PID) / Phosphotyrosine interaction domain (PID) profile. / Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain / PTB/PI domain / Variant SH3 domain / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Src homology 3 domains / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / PH-like domain superfamily / 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 domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-73Q / Mitogen-activated protein kinase 8 / C-Jun-amino-terminal kinase-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsAbad-Zapatero, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Synthesis and SAR of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as novel, selective c-Jun N-terminal kinase inhibitors.
Authors: Liu, M. / Xin, Z. / Clampit, J.E. / Wang, S. / Gum, R.J. / Haasch, D.L. / Trevillyan, J.M. / Abad-Zapatero, C. / Fry, E.H. / Sham, H.L. / Liu, G.
History
DepositionFeb 10, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Mar 14, 2018Group: Database references / Category: struct_ref_seq_dif / Item: _struct_ref_seq_dif.details
Revision 1.4Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 999SEQUENCE THE NATIVE, UNMUTATED SEQUENCE IS THE SAME AS THE P45983-2 ISOFORM. THE INTRODUCED ...SEQUENCE THE NATIVE, UNMUTATED SEQUENCE IS THE SAME AS THE P45983-2 ISOFORM. THE INTRODUCED MUTATIONS (THR183>GLU, TYR185>GLU) ARE INTENDED TO MIMIC THE ACTIVATED FORM OF THE KINASE UPON PHOSPHORYLATION OF THOSE TWO RESIDUES.

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Mitogen-activated protein kinase 8
F: C-jun-amino-terminal kinase-interacting protein 1
B: Mitogen-activated protein kinase 8
G: C-jun-amino-terminal kinase-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,44210
Polymers88,5304
Non-polymers9126
Water00
1
A: Mitogen-activated protein kinase 8
F: C-jun-amino-terminal kinase-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,7215
Polymers44,2652
Non-polymers4563
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2090 Å2
ΔGint-39 kcal/mol
Surface area16950 Å2
MethodPISA
2
B: Mitogen-activated protein kinase 8
G: C-jun-amino-terminal kinase-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,7215
Polymers44,2652
Non-polymers4563
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2210 Å2
ΔGint-37 kcal/mol
Surface area16980 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5780 Å2
ΔGint-100 kcal/mol
Surface area32440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)150.622, 150.622, 118.996
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

-
Components

#1: Protein Mitogen-activated protein kinase 8 / Stress-activated protein kinase JNK1 / c-Jun N-terminal kinase 1 / JNK-46


Mass: 42919.559 Da / Num. of mol.: 2 / Fragment: JNK1-(1-364)-6His / Mutation: T183E, Y185E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK8, JNK1, PRKM8 / Production host: Escherichia coli (E. coli) / References: UniProt: P45983, EC: 2.7.1.37
#2: Protein/peptide C-jun-amino-terminal kinase-interacting protein 1 / JNK-interacting protein 1 / JIP-1 / JNK MAP kinase scaffold protein 1 / Islet-brain-1 / IB-1 / ...JNK-interacting protein 1 / JIP-1 / JNK MAP kinase scaffold protein 1 / Islet-brain-1 / IB-1 / Mitogen-activated protein kinase 8-interacting protein 1


Mass: 1345.612 Da / Num. of mol.: 2 / Fragment: PepJIP1 / Source method: obtained synthetically
Details: The sequence is found naturally in Homo sapiens (human).
References: UniProt: Q9UQF2
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-73Q / 6-CHLORO-9-HYDROXY-1,3-DIMETHYL-1,9-DIHYDRO-4H-PYRAZOLO[3,4-B]QUINOLIN-4-ONE


Mass: 263.680 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H10ClN3O2

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 4.4 Å3/Da / Density % sol: 72.04 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: Protein was preincubated with the JIP1 peptide at a 5x molar excess. Protein concentration 9-12.6 mg/mL. Hanging drops consisted of 2uL protein plus 2uL well solution over 1 mL of well ...Details: Protein was preincubated with the JIP1 peptide at a 5x molar excess. Protein concentration 9-12.6 mg/mL. Hanging drops consisted of 2uL protein plus 2uL well solution over 1 mL of well solution. Well solution: 2.8-3.1 M Ammonium Sulfate, 10-14% glycerol. For Co-crystallization experiment compound was dissolved in DMSO at 100 mM concentration. Allow to incubate for at least an hour on ice. Solution was spun for 5 minutes at 2000g prior to setting up for crystallization. , pH 6.2, VAPOR DIFFUSION, HANGING DROP, temperature 277.0K

-
Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 18, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 3.5→20 Å / Num. all: 19322 / Num. obs: 15793 / % possible obs: 81.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 5.8 % / Biso Wilson estimate: 46.2 Å2 / Rmerge(I) obs: 0.065 / Rsym value: 0.065 / Net I/σ(I): 27.9
Reflection shellResolution: 3.5→3.62 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.365 / Mean I/σ(I) obs: 2.6 / Num. unique all: 1859 / Rsym value: 0.365 / % possible all: 63.7

-
Processing

Software
NameVersionClassification
CNX2002refinement
SDMSdata reduction
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1jnk, JNK3 KINASE

1jnk


Resolution: 3.5→19.89 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 318422.57 / Data cutoff low absF: 0 / Isotropic thermal model: GROUP / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.354 1526 9.8 %RANDOM
Rwork0.283 ---
all0.296 19322 --
obs0.286 15493 77.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 10 Å2 / ksol: 0.184616 e/Å3
Displacement parametersBiso mean: 85.1 Å2
Baniso -1Baniso -2Baniso -3
1--8.5 Å227.59 Å20 Å2
2---8.5 Å20 Å2
3---17 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.65 Å0.55 Å
Luzzati d res low-6 Å
Luzzati sigma a1.36 Å0.99 Å
Refinement stepCycle: LAST / Resolution: 3.5→19.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5862 0 56 0 5918
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.8
X-RAY DIFFRACTIONc_improper_angle_d0.99
LS refinement shellResolution: 3.5→3.62 Å / Rfactor Rfree error: 0.047 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.447 92 9.9 %
Rwork0.472 840 -
obs--47.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1ACCELRYS_CNX_TOPPAR:protein_rep.paramprotein.top
X-RAY DIFFRACTION2ACCELRYS_CNX_TOPPAR:water_rep.paramion.top
X-RAY DIFFRACTION3ACCELRYS_CNX_TOPPAR:ion.param737.top
X-RAY DIFFRACTION4737.parso4.par
X-RAY DIFFRACTION5so4.par

+
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