[English] 日本語
Yorodumi
- PDB-2no3: Novel 4-anilinopyrimidines as potent JNK1 Inhibitors -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 2no3
TitleNovel 4-anilinopyrimidines as potent JNK1 Inhibitors
Components
  • C-JUN-AMINO-TERMINAL KINASE-INTERACTING protein 1
  • Mitogen-activated protein kinase 8
KeywordsSIGNALING PROTEIN/INHIBITOR / JNK1 / C-JUN N-TERMINAL KINASE / JNK1 INHIBITORS / ANILINOPYRIMIDINES JNK1 INHIBITORS / SIGNALING PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


positive regulation of cell killing / JUN phosphorylation / regulation of DNA replication origin binding / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / protein serine/threonine kinase binding ...positive regulation of cell killing / JUN phosphorylation / regulation of DNA replication origin binding / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / protein serine/threonine kinase binding / positive regulation of cyclase activity / histone deacetylase regulator activity / positive regulation of NLRP3 inflammasome complex assembly / DSCAM interactions / NRAGE signals death through JNK / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / regulation of macroautophagy / mitogen-activated protein kinase / stress-activated MAPK cascade / response to mechanical stimulus / response to UV / JNK cascade / cellular response to cadmium ion / cellular response to amino acid starvation / positive regulation of protein metabolic process / NRIF signals cell death from the nucleus / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / negative regulation of protein binding / FCERI mediated MAPK activation / peptidyl-threonine phosphorylation / regulation of circadian rhythm / cellular response to reactive oxygen species / cellular response to mechanical stimulus / histone deacetylase binding / rhythmic process / regulation of protein localization / cellular senescence / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / cellular response to oxidative stress / protein phosphatase binding / peptidyl-serine phosphorylation / Oxidative Stress Induced Senescence / cellular response to lipopolysaccharide / response to oxidative stress / positive regulation of apoptotic process / axon / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / synapse / positive regulation of gene expression / negative regulation of apoptotic process / enzyme binding / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase, JNK / 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 ...Mitogen-activated protein (MAP) kinase, JNK / 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 domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-859 / Mitogen-activated protein kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsAbad-Zapatero, C.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Authors: Liu, M. / Wang, S. / Clampit, J.E. / Gum, R.J. / Haasch, D.L. / Rondinone, C.M. / Trevillyan, J.M. / Abad-Zapatero, C. / Fry, E.H. / Sham, H.L. / Liu, G.
#1: Journal: 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.
#2: Journal: J.Med.Chem. / Year: 2006
Title: Selective aminopyridine-based C-Jun N-terminal kinase inhibitors with cellular activiy
Authors: Szczepankiewicz, B.G. / Kosogof, C. / Nelson, L.T.J. / Liu, G. / Zhao, H. / Serby, M.D. / Xin, Z. / Liu, B. / Gum, R.J. / Haasch, D.
#3: Journal: J.Med.Chem. / Year: 2006
Title: Discovery of Potent, Highly Selective and orally bioavailable Pyridine Carboxamide C-jun NH2-terminal kinase inhibitors
Authors: Zhao, H. / Serby, M.D. / Xin, Z. / Szczepankiewicz, B.G. / Liu, M. / Kosogof, C. / Liu, B. / Gum, R.J. / Clampit, J.E. / Haasch, D.L.
History
DepositionOct 24, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / 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
Revision 1.5Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
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)89,55710
Polymers88,5304
Non-polymers1,0276
Water0
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)44,7795
Polymers44,2652
Non-polymers5133
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2280 Å2
ΔGint-43 kcal/mol
Surface area16770 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)44,7795
Polymers44,2652
Non-polymers5133
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2410 Å2
ΔGint-39 kcal/mol
Surface area17210 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6040 Å2
ΔGint-103 kcal/mol
Surface area32630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)157.201, 157.201, 123.362
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 residues 1-364 / Mutation: T183E, Y183E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK8, JNK1, PRKM8 / Plasmid: PET28A / Production host: Escherichia coli (E. coli)
References: UniProt: P45983, mitogen-activated protein kinase
#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 PEPTIDE / Source method: obtained synthetically / Details: The sequence is found naturally in homo sapiens
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-859 / 2-({2-[(3-HYDROXYPHENYL)AMINO]PYRIMIDIN-4-YL}AMINO)BENZAMIDE


Mass: 321.333 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H15N5O2

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 4.97 Å3/Da / Density % sol: 75.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion / 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 2 UL WELL SOLUTION. WELL SOLUTION:2.8-3. ...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 2 UL WELL SOLUTION. WELL SOLUTION:2.8-3.1 M AMMONIUM SULFATE, 10- 14% GLYCEROL. FOR CO-CRYSTALLIZATION EXPERIMENT WITH THE COMPOUND, THE 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 6.20, VAPOR DIFFUSION, temperature 277.0K

-
Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jan 6, 2005 / Details: Osmic Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3.2→20 Å / Num. all: 28588 / Num. obs: 27814 / % possible obs: 94.5 % / Observed criterion σ(I): 1 / Redundancy: 5.6 % / Biso Wilson estimate: 36.8 Å2 / Rmerge(I) obs: 0.083 / Rsym value: 0.083 / Net I/σ(I): 15.3
Reflection shellResolution: 3.2→3.31 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.454 / Mean I/σ(I) obs: 1.6 / Num. unique all: 2866 / Rsym value: 0.812 / % possible all: 98.3

-
Processing

Software
NameVersionClassification
CNX2002refinement
MAR345CCDdata collection
HKL-2000data reduction
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: entry 2h96

2h96


Resolution: 3.2→19.98 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 162862.68 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.276 2180 9.9 %RANDOM
Rwork0.206 ---
all0.2332 ---
obs0.2332 22039 75.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 24.1807 Å2 / ksol: 0.224291 e/Å3
Displacement parametersBiso mean: 65.1 Å2
Baniso -1Baniso -2Baniso -3
1-7.93 Å222.73 Å20 Å2
2--7.93 Å20 Å2
3----15.87 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.48 Å0.35 Å
Luzzati d res low-8 Å
Luzzati sigma a0.44 Å0.34 Å
Refinement stepCycle: LAST / Resolution: 3.2→19.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5897 0 68 0 5965
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.3
X-RAY DIFFRACTIONc_improper_angle_d0.83
LS refinement shellResolution: 3.2→3.31 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.335 153 11.6 %
Rwork0.278 1163 -
obs-1564 45.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1ACCELRYS_CNX_TOPPAR:protein_rep.paramprotein.top
X-RAY DIFFRACTION2gcr.pargcr.top
X-RAY DIFFRACTION3ACCELRYS_CNX_TOPPAR:ion.paramACCELRYS_CNX_TOPPAR:ion.param
X-RAY DIFFRACTION4859.par859.top
X-RAY DIFFRACTION5so4.parso4.top

+
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