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PDBsum entry 4j6i

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protein ligands links
Transferase/transferase inhibitor PDB id
4j6i
Jmol
Contents
Protein chain
833 a.a.
Ligands
1JV
PDB id:
4j6i
Name: Transferase/transferase inhibitor
Title: Discovery of thiazolobenzoxepin pi3-kinase inhibitors that s pi3-kinase beta isoform
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: p110 gamma, pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.90Å     R-factor:   0.208     R-free:   0.251
Authors: J.M.Murray,L.Rouge,P.Wu
Key ref: S.T.Staben et al. (2013). Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform. Bioorg Med Chem Lett, 23, 2606-2613. PubMed id: 23540645 DOI: 10.1016/j.bmcl.2013.02.102
Date:
11-Feb-13     Release date:   28-Aug-13    
PROCHECK
Go to PROCHECK summary
 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.
833 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.2013.02.102 Bioorg Med Chem Lett 23:2606-2613 (2013)
PubMed id: 23540645  
 
 
Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform.
S.T.Staben, C.Ndubaku, N.Blaquiere, M.Belvin, R.J.Bull, D.Dudley, K.Edgar, D.Gray, R.Heald, T.P.Heffron, G.E.Jones, M.Jones, A.Kolesnikov, L.Lee, J.Lesnick, C.Lewis, J.Murray, N.J.McLean, J.Nonomiya, A.G.Olivero, R.Ord, J.Pang, S.Price, W.W.Prior, L.Rouge, L.Salphati, D.Sampath, J.Wallin, L.Wang, B.Wei, C.Weismann, P.Wu.
 
  ABSTRACT  
 
A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented.