4G31

Crystal Structure of GSK6414 Bound to PERK (R587-R1092, delete A660-T867) at 2.28 A Resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK).

Axten, J.M.Medina, J.R.Feng, Y.Shu, A.Romeril, S.P.Grant, S.W.Li, W.H.Heerding, D.A.Minthorn, E.Mencken, T.Atkins, C.Liu, Q.Rabindran, S.Kumar, R.Hong, X.Goetz, A.Stanley, T.Taylor, J.D.Sigethy, S.D.Tomberlin, G.H.Hassell, A.M.Kahler, K.M.Shewchuk, L.M.Gampe, R.T.

(2012) J Med Chem 55: 7193-7207

  • DOI: https://doi.org/10.1021/jm300713s
  • Primary Citation of Related Structures:  
    4G31, 4G34

  • PubMed Abstract: 

    Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.


  • Organizational Affiliation

    Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development, Collegeville, Pennsylvania 19426, United States. Jeffrey.M.Axten@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Eukaryotic translation initiation factor 2-alpha kinase 3299Homo sapiensMutation(s): 0 
Gene Names: EIF2AK3PEKPERK
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NZJ5 (Homo sapiens)
Explore Q9NZJ5 
Go to UniProtKB:  Q9NZJ5
PHAROS:  Q9NZJ5
GTEx:  ENSG00000172071 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NZJ5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0WH
Query on 0WH

Download Ideal Coordinates CCD File 
C [auth A]1-[5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-indol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone
C24 H20 F3 N5 O
SIXVRXARNAVBTC-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
B [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0WH PDBBind:  4G31 IC50: 0.4 (nM) from 1 assay(s)
BindingDB:  4G31 IC50: min: 0.4, max: 30 (nM) from 2 assay(s)
Binding MOAD:  4G31 IC50: 0.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.119α = 90
b = 101.119β = 90
c = 158.831γ = 120
Software Package:
Software NamePurpose
MD2data collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-08
    Type: Initial release
  • Version 1.1: 2012-09-05
    Changes: Database references
  • Version 1.2: 2017-07-26
    Changes: Source and taxonomy
  • Version 1.3: 2017-11-15
    Changes: Refinement description
  • Version 1.4: 2024-02-28
    Changes: Data collection, Database references, Derived calculations