3V6R

Discovery of potent and selective covalent inhibitors of JNK


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.210 

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Literature

Discovery of potent and selective covalent inhibitors of JNK.

Zhang, T.Inesta-Vaquera, F.Niepel, M.Zhang, J.Ficarro, S.B.Machleidt, T.Xie, T.Marto, J.A.Kim, N.Sim, T.Laughlin, J.D.Park, H.LoGrasso, P.V.Patricelli, M.Nomanbhoy, T.K.Sorger, P.K.Alessi, D.R.Gray, N.S.

(2012) Chem Biol 19: 140-154

  • DOI: https://doi.org/10.1016/j.chembiol.2011.11.010
  • Primary Citation of Related Structures:  
    3V6R, 3V6S

  • PubMed Abstract: 

    The mitogen-activated kinases JNK1/2/3 are key enzymes in signaling modules that transduce and integrate extracellular stimuli into coordinated cellular response. Here, we report the discovery of irreversible inhibitors of JNK1/2/3. We describe two JNK3 cocrystal structures at 2.60 and 2.97 Å resolution that show the compounds form covalent bonds with a conserved cysteine residue. JNK-IN-8 is a selective JNK inhibitor that inhibits phosphorylation of c-Jun, a direct substrate of JNK, in cells exposed to submicromolar drug in a manner that depends on covalent modification of the conserved cysteine residue. Extensive biochemical, cellular, and pathway-based profiling establish the selectivity of JNK-IN-8 for JNK and suggests that the compound will be broadly useful as a pharmacological probe of JNK-dependent signal transduction. Potential lead compounds have also been identified for kinases, including IRAK1, PIK3C3, PIP4K2C, and PIP5K3.


  • Organizational Affiliation

    Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 10
A, B
364Homo 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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CQQ
Query on CQQ

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-{[4-(dimethylamino)butanoyl]amino}-N-(3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide
C28 H29 N7 O2
UHHXMHJPSLUZFX-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CQQ PDBBind:  3V6R IC50: 709 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.210 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.297α = 90
b = 157.259β = 90
c = 44.108γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
MOLREPphasing
BUSTERrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-01
    Type: Initial release
  • Version 1.1: 2012-07-25
    Changes: Database references