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PDBsum entry 3zim

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protein ligands links
Transferase PDB id
3zim
Jmol
Contents
Protein chain
886 a.a.
Ligands
KKR
Waters ×7
PDB id:
3zim
Name: Transferase
Title: Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase pi3kalpha
Structure: Phosphatidylinositol 4,5-bisphosphate 3-kinase ca subunit alpha isoform. Chain: a. Fragment: n-terminal truncated, residues 107-1046. Synonym: pi3-kinase subunit alpha, pi3k-alpha, pi3kalpha, ptdins-3-kinase subunit alpha, phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kda catalytic subunit alpha, ptdins-3-kinase subunit p110-alpha, p110alpha, phosphoinositide-3-kinase catalytic alpha polypeptide,
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.85Å     R-factor:   0.214     R-free:   0.278
Authors: M.Nacht,L.Qiao,M.P.Sheets,T.S.Martin,M.Labenski,H.Mazdiyasni Z.Zhu,P.Chaturvedi,D.Bhavsar,D.Niu,W.Westlin,R.C.Petter, A.P.Medikonda,A.Jestel,M.Blaesse,J.Singh
Key ref: M.Nacht et al. (2013). Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα. J Med Chem, 56, 712-721. PubMed id: 23360348 DOI: 10.1021/jm3008745
Date:
09-Jan-13     Release date:   13-Feb-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P42336  (PK3CA_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1068 a.a.
886 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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: 10.1021/jm3008745 J Med Chem 56:712-721 (2013)
PubMed id: 23360348  
 
 
Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα.
M.Nacht, L.Qiao, M.P.Sheets, T.St Martin, M.Labenski, H.Mazdiyasni, R.Karp, Z.Zhu, P.Chaturvedi, D.Bhavsar, D.Niu, W.Westlin, R.C.Petter, A.P.Medikonda, J.Singh.
 
  ABSTRACT  
 
PI3Kα has been identified as an oncogene in human tumors. By use of rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3Kα. We demonstrate, using mass spectrometry and X-ray crystallography, that the selective inhibitor covalently modifies PI3Kα on cysteine 862 (C862), an amino acid unique to the α isoform, and that PI3Kβ, -γ, and -δ are not covalently modified. 3 is able to potently (EC(50) < 100 nM) and specifically inhibit signaling in PI3Kα-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI(50) < 100 nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3Kα, was used to investigate the duration of occupancy of 3 with PI3Kα in vivo. This is the first report of a PI3Kα-selective inhibitor, and these data demonstrate the biological impact of selectively targeting PI3Kα.