PDBsum entry 3csf

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Transferase PDB id
Protein chain
839 a.a. *
Waters ×106
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of pi3k p110gamma catalytical domain in complex with organoruthenium inhibitor dw2
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform. Chain: a. Fragment: pi3-kinase p110 subunit gamma. Synonym: pi3-kinase p110 subunit gamma, ptdins-3- kinase subunit p110, pi3k, pi3kgamma, p110-pi3k. Engineered: yes
Source: Homo sapiens. Human. Gene: pik3cg. Expressed in: spodoptera frugiperda.
2.80Å     R-factor:   0.252     R-free:   0.287
Authors: P.Xie,R.Marmorstein
Key ref: P.Xie et al. (2008). Structure-based design of an organoruthenium phosphatidyl-inositol-3-kinase inhibitor reveals a switch governing lipid kinase potency and selectivity. ACS Chem Biol, 3, 305-316. PubMed id: 18484710 DOI: 10.1021/cb800039y
09-Apr-08     Release date:   27-May-08    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P48736  (PK3CG_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
1102 a.a.
839 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.  - Phosphatidylinositol-4,5-bisphosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

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
+ 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
+ 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
   Enzyme class 3: E.C.  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ 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  


DOI no: 10.1021/cb800039y ACS Chem Biol 3:305-316 (2008)
PubMed id: 18484710  
Structure-based design of an organoruthenium phosphatidyl-inositol-3-kinase inhibitor reveals a switch governing lipid kinase potency and selectivity.
P.Xie, D.S.Williams, G.E.Atilla-Gokcumen, L.Milk, M.Xiao, K.S.Smalley, M.Herlyn, E.Meggers, R.Marmorstein.
Mutations that constitutively activate the phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, including alterations in PI3K, PTEN, and AKT, are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other related diseases. In this study, we report on the combination of a novel organometallic kinase inhibitor scaffold with structure-based design to develop a PI3K inhibitor, called E5E2, with an IC 50 potency in the mid-low-nanomolar range and selectivity against a panel of protein kinases. We also show that E5E2 inhibits phospho-AKT in human melanoma cells and leads to growth inhibition. Consistent with a role for the PI3K pathway in tumor cell invasion, E5E2 treatment also inhibits the migration of melanoma cells in a 3D spheroid assay. The structure of the PI3Kgamma/E5E2 complex reveals the molecular features that give rise to this potency and selectivity toward lipid kinases with implications for the design of a subsequent generation of PI3K-isoform-specific organometallic inhibitors.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20821241 G.E.Atilla-Gokcumen, L.Di Costanzo, and E.Meggers (2011).
Structure of anticancer ruthenium half-sandwich complex bound to glycogen synthase kinase 3β.
  J Biol Inorg Chem, 16, 45-50.
PDB code: 3m1s
20148286 C.Y.Liew, X.H.Ma, and C.W.Yap (2010).
Consensus model for identification of novel PI3K inhibitors in large chemical library.
  J Comput Aided Mol Des, 24, 131-141.  
20221888 P.Heffeter, K.Böck, B.Atil, M.A.Reza Hoda, W.Körner, C.Bartel, U.Jungwirth, B.K.Keppler, M.Micksche, W.Berger, and G.Koellensperger (2010).
Intracellular protein binding patterns of the anticancer ruthenium drugs KP1019 and KP1339.
  J Biol Inorg Chem, 15, 737-748.  
19962457 S.B.Gabelli, D.Mandelker, O.Schmidt-Kittler, B.Vogelstein, and L.M.Amzel (2010).
Somatic mutations in PI3Kalpha: structural basis for enzyme activation and drug design.
  Biochim Biophys Acta, 1804, 533-540.  
19225621 E.Meggers (2009).
Targeting proteins with metal complexes.
  Chem Commun (Camb), (), 1001-1010.  
19715312 K.L.Haas, and K.J.Franz (2009).
Application of metal coordination chemistry to explore and manipulate cell biology.
  Chem Rev, 109, 4921-4960.  
19886617 N.Pagano, E.Y.Wong, T.Breiding, H.Liu, A.Wilbuer, H.Bregman, Q.Shen, S.L.Diamond, and E.Meggers (2009).
From imide to lactam metallo-pyridocarbazoles: distinct scaffolds for the design of selective protein kinase inhibitors.
  J Org Chem, 74, 8997-9009.  
19371126 P.Xie, C.Streu, J.Qin, H.Bregman, N.Pagano, E.Meggers, and R.Marmorstein (2009).
The crystal structure of BRAF in complex with an organoruthenium inhibitor reveals a mechanism for inhibition of an active form of BRAF kinase.
  Biochemistry, 48, 5187-5198.
PDB code: 3q4c
19226137 R.Anand, J.Maksimoska, N.Pagano, E.Y.Wong, P.A.Gimotty, S.L.Diamond, E.Meggers, and R.Marmorstein (2009).
Toward the development of a potent and selective organoruthenium mammalian sterile 20 kinase inhibitor.
  J Med Chem, 52, 1602-1611.  
19225663 T.J.Sundstrom, A.C.Anderson, and D.L.Wright (2009).
Inhibitors of phosphoinositide-3-kinase: a structure-based approach to understanding potency and selectivity.
  Org Biomol Chem, 7, 840-850.  
19035373 G.E.Atilla-Gokcumen, N.Pagano, C.Streu, J.Maksimoska, P.Filippakopoulos, S.Knapp, and E.Meggers (2008).
Extremely tight binding of a ruthenium complex to glycogen synthase kinase 3.
  Chembiochem, 9, 2933-2936.
PDB code: 2jld
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.