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PDBsum entry 4g11

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protein ligands links
Transferase/transferase inhibitor PDB id
4g11
Jmol
Contents
Protein chain
836 a.a.
Ligands
0W7
PDB id:
4g11
Name: Transferase/transferase inhibitor
Title: X-ray structure of pi3k-gamma bound to a 4-(morpholin-4-yl)- 6-dihydropyrimidin-2-yl)amide inhibitor
Structure: Phosphatidylinositol 4,5-bisphosphate 3-kinase ca subunit gamma isoform. Chain: a. Fragment: unp residues 144-1102. Synonym: pi3-kinase subunit gamma, pi3k-gamma, pi3kgamma, p kinase subunit gamma, phosphatidylinositol 4,5-bisphosphate 110 kda catalytic subunit gamma, ptdins-3-kinase subunit p1 p110gamma, phosphoinositide-3-kinase catalytic gamma polype serine/threonine protein kinase pik3cg, p120-pi3k.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
3.40Å     R-factor:   0.285     R-free:   0.349
Authors: R.Morales
Key ref: V.Certal et al. (2012). Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors. Bioorg Med Chem Lett, 22, 6381-6384. PubMed id: 22981333 DOI: 10.1016/j.bmcl.2012.08.072
Date:
10-Jul-12     Release date:   14-Nov-12    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P48736  (PK3CG_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1102 a.a.
836 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 2: E.C.2.7.1.153  - Phosphatidylinositol-4,5-bisphosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
1-Phosphatidyl-myo-inositol Metabolism
      Reaction: ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
ATP
+ 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
= ADP
+ 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
   Enzyme class 3: 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
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     phosphatidylinositol-mediated signaling   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     2 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.bmcl.2012.08.072 Bioorg Med Chem Lett 22:6381-6384 (2012)
PubMed id: 22981333  
 
 
Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors.
V.Certal, F.Halley, A.Virone-Oddos, F.Thompson, B.Filoche-Rommé, Y.El-Ahmad, J.C.Carry, C.Delorme, A.Karlsson, P.Y.Abecassis, L.Vincent, H.Bonnevaux, J.P.Nicolas, R.Morales, N.Michot, I.Vade, A.Louboutin, S.Perron, G.Doerflinger, B.Tric, S.Monget, C.Lengauer, L.Schio.
 
  ABSTRACT  
 
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.