5J7B

The identification and pharmacological characterization of 6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a highly potent and selective inhibitor of RIP2 Kinase, GSK583 complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.53 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.

Haile, P.A.Votta, B.J.Marquis, R.W.Bury, M.J.Mehlmann, J.F.Singhaus, R.Charnley, A.K.Lakdawala, A.S.Convery, M.A.Lipshutz, D.B.Desai, B.M.Swift, B.Capriotti, C.A.Berger, S.B.Mahajan, M.K.Reilly, M.A.Rivera, E.J.Sun, H.H.Nagilla, R.Beal, A.M.Finger, J.N.Cook, M.N.King, B.W.Ouellette, M.T.Totoritis, R.D.Pierdomenico, M.Negroni, A.Stronati, L.Cucchiara, S.Ziokowski, B.Vossenkamper, A.MacDonald, T.T.Gough, P.J.Bertin, J.Casillas, L.N.

(2016) J Med Chem 59: 4867-4880

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00211
  • Primary Citation of Related Structures:  
    5J79, 5J7B

  • PubMed Abstract: 

    RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.


  • Organizational Affiliation

    Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre , Stevenage, SG1 2NY, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Receptor-interacting serine/threonine-protein kinase 2
A, B
326Homo sapiensMutation(s): 0 
Gene Names: RIPK2CARDIAKRICKRIP2UNQ277/PRO314/PRO34092
EC: 2.7.11.1 (PDB Primary Data), 2.7.10.2 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for O43353 (Homo sapiens)
Explore O43353 
Go to UniProtKB:  O43353
PHAROS:  O43353
GTEx:  ENSG00000104312 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO43353
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6GD
Query on 6GD

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
6-(tert-butylsulfonyl)-N-(5-fluoro-2H-indazol-3-yl)quinolin-4-amine
C20 H19 F N4 O2 S
XLOGLWKOHPIJLV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.53 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 132.381α = 90
b = 132.381β = 90
c = 107.28γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-05-18
    Type: Initial release
  • Version 1.1: 2016-06-08
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description