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PDBsum entry 2uw0
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protein ligands Protein-protein interface(s) links
Transferase/inhibitor PDB id
2uw0

 

 

 

 

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Contents
Protein chains
337 a.a. *
20 a.a. *
Ligands
GVK
Waters ×302
* Residue conservation analysis
PDB id:
2uw0
Name: Transferase/inhibitor
Title: Structure of pka-pkb chimera complexed with 6-(4-(4-(4-chloro-phenyl) -piperidin-4-yl)-phenyl)-9h-purine
Structure: Camp-dependent protein kinase, alpha-catalytic subunit. Chain: a. Synonym: protein kinase a, pka c-alpha. Engineered: yes. Mutation: yes. Camp-dependent protein kinase inhibitor alpha. Chain: i. Fragment: residues 5-24. Synonym: pki, pki-alpha, muscle/brain isoform.
Source: Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606
Resolution:
2.00Å     R-factor:   0.204     R-free:   0.248
Authors: T.G.Davies,A.Donald,T.Mchardy,M.G.Rowlands,L.J.Hunter,R.G.Boyle, G.W.Aherne,M.D.Garrett,I.Collins
Key ref: A.Donald et al. (2007). Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design. J Med Chem, 50, 2289-2292. PubMed id: 17451235
Date:
15-Mar-07     Release date:   08-May-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha from Bos taurus
Seq:
Struc: 		351 a.a.
337 a.a.*
Protein chain
Pfam   ArchSchema ?
P61925  (IPKA_HUMAN) -  cAMP-dependent protein kinase inhibitor alpha from Homo sapiens
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:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
J Med Chem 50:2289-2292 (2007)
PubMed id: 17451235  
 
 
Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design.
A.Donald, T.McHardy, M.G.Rowlands, L.J.Hunter, T.G.Davies, V.Berdini, R.G.Boyle, G.W.Aherne, M.D.Garrett, I.Collins.
 
  ABSTRACT  
 
6-phenylpurines were identified as novel, ATP-competitive inhibitors of protein kinase B (PKB/Akt) from a fragment-based screen and were rapidly progressed to potent compounds using iterative protein-ligand crystallography with a PKA-PKB chimeric protein. An elaborated lead compound showed cell growth inhibition and effects on cellular signaling pathways characteristic of PKB inhibition.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20471246 C.W.Murray, and T.L.Blundell (2010).
Structural biology in fragment-based drug design.
  Curr Opin Struct Biol, 20, 497-507.  
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
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.  
19220318 A.G.Villaseñor, R.Kondru, H.Ho, S.Wang, E.Papp, D.Shaw, J.W.Barnett, M.F.Browner, and A.Kuglstatter (2009).
Structural insights for design of potent spleen tyrosine kinase inhibitors from crystallographic analysis of three inhibitor complexes.
  Chem Biol Drug Des, 73, 466-470.
PDB codes: 3fqe 3fqh 3fqs
  20616901 E.Calvo, V.Bolós, and E.Grande (2009).
Multiple roles and therapeutic implications of Akt signaling in cancer.
  Onco Targets Ther, 2, 135-150.  
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
18299817 J.Y.Lee, M.H.Rhee, and J.Y.Cho (2008).
Novel modulatory effects of SDZ 62-434 on inflammatory events in activated macrophage-like and monocytic cells.
  Naunyn Schmiedebergs Arch Pharmacol, 377, 111-124.  
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.

 

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