2JDS

Structure of cAMP-dependent protein kinase complexed with A-443654


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.211 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A Structural Comparison of Inhibitor Binding to Pkb, Pka and Pka-Pkb Chimera

Davies, T.G.Verdonk, M.L.Graham, B.Saalau-Bethell, S.Hamlett, C.C.F.Mchardy, T.Collins, I.Garrett, M.D.Workman, P.Woodhead, S.J.Jhoti, H.Barford, D.

(2007) J Mol Biol 367: 882

  • DOI: https://doi.org/10.1016/j.jmb.2007.01.004
  • Primary Citation of Related Structures:  
    2JDO, 2JDR, 2JDS, 2JDT, 2JDV

  • PubMed Abstract: 

    Although the crystal structure of the anti-cancer target protein kinase B (PKBbeta/Akt-2) has been useful in guiding inhibitor design, the closely related kinase PKA has generally been used as a structural mimic due to its facile crystallization with a range of ligands. The use of PKB-inhibitor crystallography would bring important benefits, including a more rigorous understanding of factors dictating PKA/PKB selectivity, and the opportunity to validate the utility of PKA-based surrogates. We present a "back-soaking" method for obtaining PKBbeta-ligand crystal structures, and provide a structural comparison of inhibitor binding to PKB, PKA, and PKA-PKB chimera. One inhibitor presented here exhibits no PKB/PKA selectivity, and the compound adopts a similar binding mode in all three systems. By contrast, the PKB-selective inhibitor A-443654 adopts a conformation in PKB and PKA-PKB that differs from that with PKA. We provide a structural explanation for this difference, and highlight the ability of PKA-PKB to mimic the true PKB binding mode in this case.


  • Organizational Affiliation

    Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. t.davies@astex-therapeutics.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CAMP-DEPENDENT PROTEIN KINASE351Bos taurusMutation(s): 0 
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]20Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P61925 (Homo sapiens)
Explore P61925 
Go to UniProtKB:  P61925
PHAROS:  P61925
GTEx:  ENSG00000171033 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61925
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
L20
Query on L20

Download Ideal Coordinates CCD File 
C [auth A](2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE
C24 H23 N5 O
YWTBGJGMTBHQTM-IBGZPJMESA-N
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
Binding Affinity Annotations 
IDSourceBinding Affinity
L20 PDBBind:  2JDS Ki: 6.3 (nM) from 1 assay(s)
Binding MOAD:  2JDS Ki: 6.3 (nM) from 1 assay(s)
BindingDB:  2JDS IC50: min: 6, max: 27 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.211 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.538α = 90
b = 75.061β = 90
c = 80.133γ = 90
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2007-02-13
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description