5D9K

Rsk2 N-terminal Kinase in Complex with BI-D1870


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Potent and Selective RSK Inhibitors as Biological Probes.

Jain, R.Mathur, M.Lan, J.Costales, A.Atallah, G.Ramurthy, S.Subramanian, S.Setti, L.Feucht, P.Warne, B.Doyle, L.Basham, S.Jefferson, A.B.Lindvall, M.Appleton, B.A.Shafer, C.M.

(2015) J Med Chem 58: 6766-6783

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00450
  • Primary Citation of Related Structures:  
    5D9K, 5D9L

  • PubMed Abstract: 

    While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridine inhibitors of the RSK kinase family as demonstrated cellularly by the inhibition of YB1 phosphorylation. These compounds provide for the first time in vitro tools with an improved selectivity and potency profile to examine the importance of RSK signaling in cancer cells and to fully evaluate RSK as a therapeutic target.


  • Organizational Affiliation

    Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Ribosomal protein S6 kinase alpha-3
A, B
330Homo sapiensMutation(s): 0 
Gene Names: RPS6KA3ISPK1MAPKAPK1BRSK2
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P51812 (Homo sapiens)
Explore P51812 
Go to UniProtKB:  P51812
PHAROS:  P51812
GTEx:  ENSG00000177189 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51812
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
584 BindingDB:  5D9K Kd: 3546 (nM) from 1 assay(s)
IC50: min: 3, max: 2.33e+4 (nM) from 11 assay(s)
EC50: min: 500, max: 2600 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 34.19α = 90
b = 53.71β = 91.75
c = 207.94γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-02
    Type: Initial release
  • Version 1.1: 2015-09-23
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations