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PDBsum entry 4l1b

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protein ligands Protein-protein interface(s) links
Signaling protein/transferase/inhibitor PDB id
4l1b
Jmol
Contents
Protein chains
994 a.a.
277 a.a.
Ligands
SO4
Waters ×37
PDB id:
4l1b
Name: Signaling protein/transferase/inhibitor
Title: Crystal structure of p110alpha complexed with nish2 of p85al
Structure: Phosphatidylinositol 4,5-bisphosphate 3-kinase ca subunit alpha isoform. Chain: a. Synonym: pi3-kinase subunit alpha, pi3k-alpha, pi3kalpha, p kinase subunit alpha, phosphatidylinositol 4,5-bisphosphate 110 kda catalytic subunit alpha, ptdins-3-kinase subunit p1 p110alpha, phosphoinositide-3-kinase catalytic alpha polype serine/threonine protein kinase pik3ca. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3ca. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: grb1, pik3r1.
Resolution:
2.59Å     R-factor:   0.220     R-free:   0.274
Authors: J.Zhang,Y.L.Zhao,Y.Y.Chen,M.Huang,F.Jiang
Key ref: Y.Zhao et al. (2014). Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design. ACS Med Chem Lett, 5, 138-142. PubMed id: 24900786 DOI: 10.1021/ml400378e
Date:
03-Jun-13     Release date:   01-Jan-14    
PROCHECK
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 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.
994 a.a.
Protein chain
Pfam   ArchSchema ?
P27986  (P85A_HUMAN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha
Seq:
Struc:
 
Seq:
Struc:
724 a.a.
277 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: Chain A: 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: Chain A: 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!
  Cellular component     plasma membrane   5 terms 
  Biological process     phosphatidylinositol-3-phosphate biosynthetic process   37 terms 
  Biochemical function     nucleotide binding     15 terms  

 

 
    reference    
 
 
DOI no: 10.1021/ml400378e ACS Med Chem Lett 5:138-142 (2014)
PubMed id: 24900786  
 
 
Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.
Y.Zhao, X.Zhang, Y.Chen, S.Lu, Y.Peng, X.Wang, C.Guo, A.Zhou, J.Zhang, Y.Luo, Q.Shen, J.Ding, L.Meng, J.Zhang.
 
  ABSTRACT  
 
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors.