6EKD

Crystal structure of JNK3 in complex with a pyridinylimidazole inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38 alpha Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.

Ansideri, F.Macedo, J.T.Eitel, M.El-Gokha, A.Zinad, D.S.Scarpellini, C.Kudolo, M.Schollmeyer, D.Boeckler, F.M.Blaum, B.S.Laufer, S.A.Koch, P.

(2018) ACS Omega 3: 7809-7831

  • DOI: https://doi.org/10.1021/acsomega.8b00668
  • Primary Citation of Related Structures:  
    6EKD, 6EMH, 6EQ9

  • PubMed Abstract: 

    Starting from known p38α mitogen-activated protein kinase (MAPK) inhibitors, a series of inhibitors of the c-Jun N-terminal kinase (JNK) 3 was obtained. Altering the substitution pattern of the pyridinylimidazole scaffold proved to be effective in shifting the inhibitory activity from the original target p38α MAPK to the closely related JNK3. In particular, a significant improvement for JNK3 selectivity could be achieved by addressing the hydrophobic region I with a small methyl group. Furthermore, additional structural modifications permitted to explore structure-activity relationships. The most potent inhibitor 4-(4-methyl-2-(methylthio)-1 H -imidazol-5-yl)- N -(4-morpholinophenyl)pyridin-2-amine showed an IC 50 value for the JNK3 in the low triple digit nanomolar range and its binding mode was confirmed by X-ray crystallography.


  • Organizational Affiliation

    Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 10367Homo sapiensMutation(s): 0 
Gene Names: MAPK10JNK3JNK3APRKM10SAPK1B
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for P53779 (Homo sapiens)
Explore P53779 
Go to UniProtKB:  P53779
PHAROS:  P53779
GTEx:  ENSG00000109339 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP53779
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
B9K (Subject of Investigation/LOI)
Query on B9K

Download Ideal Coordinates CCD File 
D [auth A]4-(4-methyl-2-methylsulfanyl-1~{H}-imidazol-5-yl)-~{N}-(4-morpholin-4-ylphenyl)pyridin-2-amine
C20 H23 N5 O S
IATSSYNKRCFJAY-UHFFFAOYSA-N
BME
Query on BME

Download Ideal Coordinates CCD File 
B [auth A]BETA-MERCAPTOETHANOL
C2 H6 O S
DGVVWUTYPXICAM-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
B9K Binding MOAD:  6EKD IC50: 184 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.51α = 90
b = 124.82β = 90
c = 68.89γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-08
    Type: Initial release
  • Version 1.1: 2018-08-22
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description