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PDBsum entry 2jdt

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2jdt
Jmol
Contents
Protein chains
336 a.a. *
20 a.a. *
Ligands
I5S
Waters ×294
* Residue conservation analysis
PDB id:
2jdt
Name: Transferase
Title: Structure of pka-pkb chimera complexed with isoquinoline-5- sulfonic acid (2-(2-(4-chlorobenzyloxy) ethylamino)ethyl) amide
Structure: Camp-dependent protein kinase. Chain: a. Synonym: protein kinase a, pka c-alpha. Engineered: yes. Mutation: yes. Other_details: alpha-catalytic subunit. Camp-dependent protein kinase inhibitor alpha. Chain: i. Fragment: residues 5-24.
Source: Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606
Resolution:
2.15Å     R-factor:   0.203     R-free:   0.259
Authors: T.G.Davies,M.L.Verdonk,B.Graham,S.Saalau-Bethell, C.C.F.Hamlett,T.Mchardy,I.Collins,M.D.Garrett,P.Workman, S.J.Woodhead,H.Jhoti,D.Barford
Key ref:
T.G.Davies et al. (2007). A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. J Mol Biol, 367, 882-894. PubMed id: 17275837 DOI: 10.1016/j.jmb.2007.01.004
Date:
12-Jan-07     Release date:   13-Feb-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha
Seq:
Struc:
351 a.a.
336 a.a.*
Protein chain
Pfam   ArchSchema ?
P61925  (IPKA_HUMAN) -  cAMP-dependent protein kinase inhibitor alpha
Seq:
Struc:
76 a.a.
20 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain A: E.C.2.7.11.11  - cAMP-dependent protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     sperm midpiece   11 terms 
  Biological process     regulation of proteasomal protein catabolic process   19 terms 
  Biochemical function     nucleotide binding     14 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.jmb.2007.01.004 J Mol Biol 367:882-894 (2007)
PubMed id: 17275837  
 
 
A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera.
T.G.Davies, M.L.Verdonk, B.Graham, S.Saalau-Bethell, C.C.Hamlett, T.McHardy, I.Collins, M.D.Garrett, P.Workman, S.J.Woodhead, H.Jhoti, D.Barford.
 
  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.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Chemical structures of 1 (isoquinoline sulphonamide) and 2 (A-443654).
Figure 5.
Figure 5. Inhibitor 2 binding to PKA and PKB. (a) PKA-2 and (b) PKB-2 (in the region of the ATP site). Final 2mF[o]–DF[c] electron density for the inhibitors is contoured at 1σ and shown in blue. (c) Superposition of PKA-2 (grey) and PKB-2 (yellow). Residues are labelled using PKB numbering. (d) Schematic diagram showing binding of 2 to PKA and PKB. Key non-covalent interactions are depicted as broken lines. The alternative positions of the indole ring are shown by shading: PKA (light grey) and PKB (black). (e) Surface representation of PKB with compound 2 bound. The surface was coloured by lipophilicity in AstexViewer^46 using the method described by Gaillard et al.,^53 with red/pink representing the most lipophilic regions, and blue/green the least lipophilic. The putative methyl-aromatic interaction discussed in the text is shown as a broken line. (f) Overlay of surfaces for PKA (grey) and PKB (yellow) with compound 2 bound. The indole group of 2 packs with the side-chain of Met282, but would leave a cavity in PKA due to the substitution by leucine at this point in the active site.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 367, 882-894) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23064647 S.Hughes, F.Elustondo, A.Di Fonzo, F.G.Leroux, A.C.Wong, A.P.Snijders, S.J.Matthews, and P.Cherepanov (2012).
Crystal structure of human CDC7 kinase in complex with its activator DBF4.
  Nat Struct Mol Biol, 19, 1101-1107.
PDB codes: 4f99 4f9a 4f9b 4f9c
20151677 T.McHardy, J.J.Caldwell, K.M.Cheung, L.J.Hunter, K.Taylor, M.Rowlands, R.Ruddle, A.Henley, A.de Haven Brandon, M.Valenti, T.G.Davies, L.Fazal, L.Seavers, F.I.Raynaud, S.A.Eccles, G.W.Aherne, M.D.Garrett, and I.Collins (2010).
Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt).
  J Med Chem, 53, 2239-2249.
PDB codes: 2x37 2x39 2xh5
20582381 T.Okuzumi, G.S.Ducker, C.Zhang, B.Aizenstein, R.Hoffman, and K.M.Shokat (2010).
Synthesis and evaluation of indazole based analog sensitive Akt inhibitors.
  Mol Biosyst, 6, 1389-1402.  
20205431 X.Zhang, A.C.Gibbs, C.H.Reynolds, M.B.Peters, and L.M.Westerhoff (2010).
Quantum mechanical pairwise decomposition analysis of protein kinase B inhibitors: validating a new tool for guiding drug design.
  J Chem Inf Model, 50, 651-661.  
19124027 I.Westwood, D.M.Cheary, J.E.Baxter, M.W.Richards, R.L.van Montfort, A.M.Fry, and R.Bayliss (2009).
Insights into the conformational variability and regulation of human Nek2 kinase.
  J Mol Biol, 386, 476-485.
PDB codes: 2w5a 2w5b 2w5h
19568781 L.A.Smyth, and I.Collins (2009).
Measuring and interpreting the selectivity of protein kinase inhibitors.
  J Chem Biol, 2, 131-151.  
19043747 M.Muddassar, F.A.Pasha, M.M.Neaz, Y.Saleem, and S.J.Cho (2009).
Elucidation of binding mode and three dimensional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors.
  J Mol Model, 15, 183-192.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
19465931 T.Okuzumi, D.Fiedler, C.Zhang, D.C.Gray, B.Aizenstein, R.Hoffman, and K.M.Shokat (2009).
Inhibitor hijacking of Akt activation.
  Nat Chem Biol, 5, 484-493.  
18165240 A.Vaid, D.C.Thomas, and P.Sharma (2008).
Role of Ca2+/calmodulin-PfPKB signaling pathway in erythrocyte invasion by Plasmodium falciparum.
  J Biol Chem, 283, 5589-5597.  
18794885 C.Garcia-Echeverria, and W.R.Sellers (2008).
Drug discovery approaches targeting the PI3K/Akt pathway in cancer.
  Oncogene, 27, 5511-5526.  
18046412 C.Kuijl, N.D.Savage, M.Marsman, A.W.Tuin, L.Janssen, D.A.Egan, M.Ketema, R.van den Nieuwendijk, S.J.van den Eeden, A.Geluk, A.Poot, G.van der Marel, R.L.Beijersbergen, H.Overkleeft, T.H.Ottenhoff, and J.Neefjes (2007).
Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1.
  Nature, 450, 725-730.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.