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PDBsum entry 4ezl

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protein ligands links
Transferase/transferase inhibitor PDB id
4ezl
Jmol
Contents
Protein chain
834 a.a.
Ligands
0SE
Waters ×1
PDB id:
4ezl
Name: Transferase/transferase inhibitor
Title: Potent and selective inhibitors of pi3k-delta: obtaining iso selectivity from the affinity pocket and tryptophan shelf
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. Expression_system_cell_line: sf9.
Resolution:
2.94Å     R-factor:   0.245     R-free:   0.271
Authors: J.M.Murray
Key ref: D.P.Sutherlin et al. (2012). Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf. Bioorg Med Chem Lett, 22, 4296-4302. PubMed id: 22672799
Date:
02-May-12     Release date:   17-Apr-13    
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.
834 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 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    
 
 
Bioorg Med Chem Lett 22:4296-4302 (2012)
PubMed id: 22672799  
 
 
Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf.
D.P.Sutherlin, S.Baker, A.Bisconte, P.M.Blaney, A.Brown, B.K.Chan, D.Chantry, G.Castanedo, P.DePledge, P.Goldsmith, D.M.Goldstein, T.Hancox, J.Kaur, D.Knowles, R.Kondru, J.Lesnick, M.C.Lucas, C.Lewis, J.Murray, A.J.Nadin, J.Nonomiya, J.Pang, N.Pegg, S.Price, K.Reif, B.S.Safina, L.Salphati, S.Staben, E.M.Seward, S.Shuttleworth, S.Sohal, Z.K.Sweeney, M.Ultsch, B.Waszkowycz, B.Wei.
 
  ABSTRACT  
 
A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.