spacer
spacer

PDBsum entry 3ow4

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
3ow4
Jmol
Contents
Protein chains
318 a.a. *
Ligands
GLY-ARG-PRO-ARG-
THR-THR-SER-PHE-
ALA-GLU
×2
SMY ×2
Waters ×171
* Residue conservation analysis
PDB id:
3ow4
Name: Transferase/transferase inhibitor
Title: Discovery of dihydrothieno- and dihydrofuropyrimidines as po akt inhibitors
Structure: Rac-alpha serine/threonine-protein kinase. Chain: a, b. Synonym: rac-pk-alpha, protein kinase b, pkb, proto-oncogen engineered: yes. Mutation: yes. Gsk 3 beta peptide. Chain: c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: akt1, pkb, rac. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes
Resolution:
2.60Å     R-factor:   0.197     R-free:   0.268
Authors: F.Dizon,W.Wu,G.P.A.Vigers,B.J.Brandhuber
Key ref: J.R.Bencsik et al. (2010). Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors. Bioorg Med Chem Lett, 20, 7037-7041. PubMed id: 20971641 DOI: 10.1016/j.bmcl.2010.09.112
Date:
17-Sep-10     Release date:   10-Nov-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P31749  (AKT1_HUMAN) -  RAC-alpha serine/threonine-protein kinase
Seq:
Struc:
480 a.a.
318 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - Non-specific serine/threonine 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!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.bmcl.2010.09.112 Bioorg Med Chem Lett 20:7037-7041 (2010)
PubMed id: 20971641  
 
 
Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.
J.R.Bencsik, D.Xiao, J.F.Blake, N.C.Kallan, I.S.Mitchell, K.L.Spencer, R.Xu, S.L.Gloor, M.Martinson, T.Risom, R.D.Woessner, F.Dizon, W.I.Wu, G.P.Vigers, B.J.Brandhuber, N.J.Skelton, W.W.Prior, L.J.Murray.
 
  ABSTRACT  
 
Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21392984 N.C.Kallan, K.L.Spencer, J.F.Blake, R.Xu, J.Heizer, J.R.Bencsik, I.S.Mitchell, S.L.Gloor, M.Martinson, T.Risom, S.D.Gross, T.H.Morales, W.I.Wu, G.P.Vigers, B.J.Brandhuber, and N.J.Skelton (2011).
Discovery and SAR of spirochromane Akt inhibitors.
  Bioorg Med Chem Lett, 21, 2410-2414.
PDB codes: 3qkk 3qkl
21420856 R.Xu, A.Banka, J.F.Blake, I.S.Mitchell, E.M.Wallace, J.R.Bencsik, N.C.Kallan, K.L.Spencer, S.L.Gloor, M.Martinson, T.Risom, S.D.Gross, T.H.Morales, W.I.Wu, G.P.Vigers, B.J.Brandhuber, and N.J.Skelton (2011).
Discovery of spirocyclic sulfonamides as potent Akt inhibitors with exquisite selectivity against PKA.
  Bioorg Med Chem Lett, 21, 2335-2340.
PDB code: 3qkm
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.