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PDBsum entry 3mjw

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protein ligands links
Transferase PDB id
3mjw
Jmol
Contents
Protein chain
819 a.a. *
Ligands
WYF
* Residue conservation analysis
PDB id:
3mjw
Name: Transferase
Title: Pi3 kinase gamma with a benzofuranone inhibitor
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase ca subunit gamma isoform. Chain: a. Fragment: pi3 kinase gamma (unp residues 144 to 1102). Synonym: ptdins-3-kinase subunit gamma, pi3-kinase subunit pi3k-gamma, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, ptdins-3-kinase subunit p110-gamma pi3k. Engineered: yes
Source: Homo sapiens. Organism_taxid: 9606. Gene: pik3cg. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.87Å     R-factor:   0.225     R-free:   0.281
Authors: J.Bard,K.Svenson
Key ref: N.Zhang et al. (2010). 5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer. Bioorg Med Chem Lett, 20, 3526-3529. PubMed id: 20483602 DOI: 10.1016/j.bmcl.2010.04.139
Date:
13-Apr-10     Release date:   09-Jun-10    
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.
819 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    
 
 
DOI no: 10.1016/j.bmcl.2010.04.139 Bioorg Med Chem Lett 20:3526-3529 (2010)
PubMed id: 20483602  
 
 
5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer.
N.Zhang, S.Ayral-Kaloustian, J.T.Anderson, T.Nguyen, S.Das, A.M.Venkatesan, N.Brooijmans, J.Lucas, K.Yu, I.Hollander, R.Mallon.
 
  ABSTRACT  
 
A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kalpha and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9.