4C33

PKA-S6K1 Chimera Apo


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.158 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.

Couty, S.Westwood, I.M.Kalusa, A.Cano, C.Travers, J.Boxall, K.Chow, C.L.Burns, S.Schmitt, J.Pickard, L.Barillari, C.McAndrew, P.C.Clarke, P.A.Linardopoulos, S.Griffin, R.J.Aherne, G.W.Raynaud, F.I.Workman, P.Jones, K.van Montfort, R.L.

(2013) Oncotarget 4: 1647-1661

  • DOI: https://doi.org/10.18632/oncotarget.1255
  • Primary Citation of Related Structures:  
    4C33, 4C34, 4C35, 4C36, 4C37, 4C38

  • PubMed Abstract: 

    The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases.


  • Organizational Affiliation

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA351Bos taurusMutation(s): 5 
EC: 2.7.11.11
UniProt
Find proteins for P00517 (Bos taurus)
Explore P00517 
Go to UniProtKB:  P00517
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00517
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHAB [auth I]18Bos taurusMutation(s): 0 
UniProt
Find proteins for Q3SX13 (Bos taurus)
Explore Q3SX13 
Go to UniProtKB:  Q3SX13
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ3SX13
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.158 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.72α = 90
b = 75.2β = 90
c = 80.12γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-09
    Type: Initial release
  • Version 1.1: 2013-11-20
    Changes: Database references
  • Version 1.2: 2019-10-09
    Changes: Data collection, Database references, Derived calculations, Other
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Refinement description