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PDBsum entry 2uw6
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protein ligands Protein-protein interface(s) links
Transferase/inhibitor PDB id
2uw6

 

 

 

 

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Contents
Protein chains
337 a.a. *
20 a.a. *
Ligands
GVO
Waters ×208
* Residue conservation analysis
PDB id:
2uw6
Name: Transferase/inhibitor
Title: Structure of pka-pkb chimera complexed with (s)-2-(4-chloro-phenyl)- 2-(4-1h-pyrazol-4-yl)-phenyl)-ethylamine
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:
2.23Å     R-factor:   0.192     R-free:   0.244
Authors: T.G.Davies,G.Saxty,S.J.Woodhead,V.Berdini,M.L.Verdonk,P.G.Wyatt, R.G.Boyle,D.Barford,R.Downham,M.D.Garrett,R.A.Carr
Key ref: G.Saxty et al. (2007). Identification of inhibitors of protein kinase B using fragment-based lead discovery. J Med Chem, 50, 2293-2296. PubMed id: 17451234
Date:
19-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 50:2293-2296 (2007)
PubMed id: 17451234  
 
 
Identification of inhibitors of protein kinase B using fragment-based lead discovery.
G.Saxty, S.J.Woodhead, V.Berdini, T.G.Davies, M.L.Verdonk, P.G.Wyatt, R.G.Boyle, D.Barford, R.Downham, M.D.Garrett, R.A.Carr.
 
  ABSTRACT  
 
Using fragment-based screening techniques, 5-methyl-4-phenyl-1H-pyrazole (IC50 80 microM) was identified as a novel, low molecular weight inhibitor of protein kinase B (PKB). Herein we describe the rapid elaboration of highly potent and ligand efficient analogues using a fragment growing approach. Iterative structure-based design was supported by protein-ligand structure determinations using a PKA-PKB "chimera" and a final protein-ligand structure of a lead compound in PKBbeta itself.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21428956 E.Cressina, L.Chen, M.Moulin, F.J.Leeper, C.Abell, and A.G.Smith (2011).
Identification of novel ligands for thiamine pyrophosphate (TPP) riboswitches.
  Biochem Soc Trans, 39, 652-657.  
  21472806 F.Lang, G.Chen, L.Li, J.Xing, F.Han, L.Cun, and J.Liao (2011).
Rhodium-catalyzed highly enantioselective addition of arylboronic acids to 2-nitrostyrenes by tert-butanesulfinylphosphine ligand.
  Chemistry, 17, 5242-5245.  
20471246 C.W.Murray, and T.L.Blundell (2010).
Structural biology in fragment-based drug design.
  Curr Opin Struct Biol, 20, 497-507.  
19774589 D.Lavogina, E.Enkvist, and A.Uri (2010).
Bisubstrate inhibitors of protein kinases: from principle to practical applications.
  ChemMedChem, 5, 23-34.  
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.  
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.  
19028598 M.Orita, K.Ohno, and T.Niimi (2009).
Two 'Golden Ratio' indices in fragment-based drug discovery.
  Drug Discov Today, 14, 321-328.  
18613071 Q.S.Du, R.B.Huang, Y.T.Wei, Z.W.Pang, L.Q.Du, and K.C.Chou (2009).
Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.
  J Comput Chem, 30, 295-304.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
18972468 C.Peifer, and D.R.Alessi (2008).
Small-molecule inhibitors of PDK1.
  ChemMedChem, 3, 1810-1838.  
18651625 M.L.Verdonk, and D.C.Rees (2008).
Group efficiency: a guideline for hits-to-leads chemistry.
  ChemMedChem, 3, 1179-1180.  
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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