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PDBsum entry 3mvh

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protein ligands metals links
Transferase PDB id
3mvh
Jmol
Contents
Protein chain
312 a.a. *
Ligands
GLY-ARG-PRO-ARG-
THR-THR-SER-PHE-
ALA-GLU
WFE
Metals
_MN
Waters ×247
* Residue conservation analysis
PDB id:
3mvh
Name: Transferase
Title: Crystal structure of akt-1-inhibitor complexes
Structure: V-akt murine thymoma viral oncogene homolog 1 (ak chain: a. Fragment: kinase domain. Engineered: yes. Mutation: yes. Gsk3-beta peptide. Chain: b. Fragment: 10-residue peptide from gsk3-b (residues 3-12). Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: akt-1, akt1. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469. Synthetic: yes
Resolution:
2.01Å     R-factor:   0.181     R-free:   0.230
Authors: J.Pandit
Key ref: K.D.Freeman-Cook et al. (2010). Design of selective, ATP-competitive inhibitors of Akt. J Med Chem, 53, 4615-4622. PubMed id: 20481595 DOI: 10.1021/jm1003842
Date:
04-May-10     Release date:   02-Jun-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P31749  (AKT1_HUMAN) -  RAC-alpha serine/threonine-protein kinase
Seq:
Struc:
480 a.a.
312 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 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: 10.1021/jm1003842 J Med Chem 53:4615-4622 (2010)
PubMed id: 20481595  
 
 
Design of selective, ATP-competitive inhibitors of Akt.
K.D.Freeman-Cook, C.Autry, G.Borzillo, D.Gordon, E.Barbacci-Tobin, V.Bernardo, D.Briere, T.Clark, M.Corbett, J.Jakubczak, S.Kakar, E.Knauth, B.Lippa, M.J.Luzzio, M.Mansour, G.Martinelli, M.Marx, K.Nelson, J.Pandit, F.Rajamohan, S.Robinson, C.Subramanyam, L.Wei, M.Wythes, J.Morris.
 
  ABSTRACT  
 
This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21439031 L.Rosenbaum, G.Hinselmann, A.Jahn, and A.Zell (2011).
Interpreting linear support vector machine models with heat map molecule coloring.
  J Cheminform, 3, 11.  
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
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