PDBsum entry 2v4l

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Transferase PDB id
Protein chain
845 a.a. *
Waters ×50
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Complex of human phosphoinositide 3-kinase catalytic subunit gamma (p110 gamma) with pik-284
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase ca subunit gamma isoform. Chain: a. Fragment: catalytic subunit, residues 144-1102. Synonym: pi3-kinase p110 subunit gamma, ptdins-3-kinase sub p110, pi3kgamma, p120-pi3k, pi3k, phosphoinositide 3-kinas engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
2.50Å     R-factor:   0.250     R-free:   0.296
Authors: B.Apsel,B.Gonzalez,J.A.Blair,T.M.Nazif,M.E.Feldman,R.L.Willi K.M.Shokat,Z.A.Knight
Key ref:
B.Apsel et al. (2008). Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol, 4, 691-699. PubMed id: 18849971 DOI: 10.1038/nchembio.117
25-Sep-08     Release date:   14-Oct-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.
845 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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: 10.1038/nchembio.117 Nat Chem Biol 4:691-699 (2008)
PubMed id: 18849971  
Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.
B.Apsel, J.A.Blair, B.Gonzalez, T.M.Nazif, M.E.Feldman, B.Aizenstein, R.Hoffman, R.L.Williams, K.M.Shokat, Z.A.Knight.
The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.
  Selected figure(s)  
Figure 2.
(a) Experimental strategy for the discovery of dual inhibitors, and IC[50] values ( M) for 8 molecules tested against 14 tyrosine kinases and PI(3)Ks (10 M ATP). IC[50] values less than 0.1 M are shaded red. Pyrazolopyrimidine N4 and N5, which make hydrogen bonds to the kinase, are labeled. (b) Percentage inhibition of 84 tyrosine kinases (right) and 135 serine-threonine kinases (left) by 7 inhibitors from this study (right columns) and 5 reference compounds (left columns). PP inhibitors were tested at 1 M drug and, typically, 10 M ATP. Data from the Invitrogen SelectScreen assay. (c) Principal component analysis of the target selectivity of 172 pyrazolopyrimidine inhibitors and 8 reference compounds. Key compounds are labeled.
Figure 4.
(a) Correlation between IC[50] values for inhibitors against Src (x axis) and either Hck or the gatekeeper mutant Src T338I (y axis). (b) Binding orientation of S1 relative to ATP in c-Src (top) and p110 (bottom). (c) Overlay of cocrystal structures of inhibitors bound to c-Src (protein colored red, drugs orange: S1, PP102, PP121 and PP494) and p110 (protein blue, compounds gray: S1 and S2). The gatekeeper residues Thr338 (c-Src) and Ile879 (p110 ) are highlighted. (d) Top, the catalytic lysine (Lys295) makes a hydrogen bond to Glu310 in active c-Src. Center, helix C and Glu310 are disordered in c-Src structures containing PP102. Bottom, PP121 makes a hydrogen bond to Glu310 and orders helix C when bound to c-Src.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2008, 4, 691-699) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21439267 A.Dormond-Meuwly, D.Roulin, M.Dufour, M.Benoit, N.Demartines, and O.Dormond (2011).
The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors.
  Biochem Biophys Res Commun, 407, 714-719.  
21428918 C.Garcia-Echeverria (2011).
Blocking the mTOR pathway: a drug discovery perspective.
  Biochem Soc Trans, 39, 451-455.  
21464312 H.Jo, P.K.Lo, Y.Li, F.Loison, S.Green, J.Wang, L.E.Silberstein, K.Ye, H.Chen, and H.R.Luo (2011).
Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination.
  Proc Natl Acad Sci U S A, 108, 6486-6491.  
21364574 H.Yabuuchi, S.Niijima, H.Takematsu, T.Ida, T.Hirokawa, T.Hara, T.Ogawa, Y.Minowa, G.Tsujimoto, and Y.Okuno (2011).
Analysis of multiple compound-protein interactions reveals novel bioactive molecules.
  Mol Syst Biol, 7, 472.  
21373195 I.Takigawa, K.Tsuda, and H.Mamitsuka (2011).
Mining significant substructure pairs for interpreting polypharmacology in drug-target network.
  PLoS One, 6, e16999.  
21208444 J.R.Brown, and K.R.Auger (2011).
Phylogenomics of phosphoinositide lipid kinases: perspectives on the evolution of second messenger signaling and drug discovery.
  BMC Evol Biol, 11, 4.  
19714578 S.Schenone, O.Bruno, M.Radi, and M.Botta (2011).
New insights into small-molecule inhibitors of Bcr-Abl.
  Med Res Rev, 31, 1.  
20944678 U.Kruse, C.P.Pallasch, M.Bantscheff, D.Eberhard, L.Frenzel, S.Ghidelli, S.K.Maier, T.Werner, C.M.Wendtner, and G.Drewes (2011).
Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells.
  Leukemia, 25, 89.  
21333749 Y.J.Zhang, Y.Duan, and X.F.Zheng (2011).
Targeting the mTOR kinase domain: the second generation of mTOR inhibitors.
  Drug Discov Today, 16, 325-331.  
20081827 A.Berndt, S.Miller, O.Williams, D.D.Le, B.T.Houseman, J.I.Pacold, F.Gorrec, W.C.Hon, Y.Liu, C.Rommel, P.Gaillard, T.Rückle, M.K.Schwarz, K.M.Shokat, J.P.Shaw, and R.L.Williams (2010).
The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
  Nat Chem Biol, 6, 117-124.
PDB codes: 2wxe 2wxf 2wxg 2wxh 2wxi 2wxj 2wxk 2wxl 2wxm 2wxn 2wxo 2wxp 2wxq 2wxr 2x38
20117850 A.Pujol, R.Mosca, J.Farrés, and P.Aloy (2010).
Unveiling the role of network and systems biology in drug discovery.
  Trends Pharmacol Sci, 31, 115-123.  
20072130 M.R.Janes, J.J.Limon, L.So, J.Chen, R.J.Lim, M.A.Chavez, C.Vu, M.B.Lilly, S.Mallya, S.T.Ong, M.Konopleva, M.B.Martin, P.Ren, Y.Liu, C.Rommel, and D.A.Fruman (2010).
Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor.
  Nat Med, 16, 205-213.  
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.  
20201075 V.R.Konda, A.Desai, G.Darland, J.S.Bland, and M.L.Tripp (2010).
META060 inhibits osteoclastogenesis and matrix metalloproteinases in vitro and reduces bone and cartilage degradation in a mouse model of rheumatoid arthritis.
  Arthritis Rheum, 62, 1683-1692.  
20094047 Z.A.Knight, H.Lin, and K.M.Shokat (2010).
Targeting the cancer kinome through polypharmacology.
  Nat Rev Cancer, 10, 130-137.  
19295628 I.D.Fraser, and R.N.Germain (2009).
Navigating the network: signaling cross-talk in hematopoietic cells.
  Nat Immunol, 10, 327-331.  
19581876 J.Lehár, A.S.Krueger, W.Avery, A.M.Heilbut, L.M.Johansen, E.R.Price, R.J.Rickles, G.F.Short, J.E.Staunton, X.Jin, M.S.Lee, G.R.Zimmermann, and A.A.Borisy (2009).
Synergistic drug combinations tend to improve therapeutically relevant selectivity.
  Nat Biotechnol, 27, 659-666.  
19295632 K.Ghoreschi, A.Laurence, and J.J.O'Shea (2009).
Selectivity and therapeutic inhibition of kinases: to be or not to be?
  Nat Immunol, 10, 356-360.  
19568781 L.A.Smyth, and I.Collins (2009).
Measuring and interpreting the selectivity of protein kinase inhibitors.
  J Chem Biol, 2, 131-151.  
19209957 M.E.Feldman, B.Apsel, A.Uotila, R.Loewith, Z.A.Knight, D.Ruggero, and K.M.Shokat (2009).
Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
  PLoS Biol, 7, e38.  
19474827 M.T.Grande, and J.M.López-Novoa (2009).
Fibroblast activation and myofibroblast generation in obstructive nephropathy.
  Nat Rev Nephrol, 5, 319-328.  
19723347 N.P.Tatonetti, T.Liu, and R.B.Altman (2009).
Predicting drug side-effects by chemical systems biology.
  Genome Biol, 10, 238.  
19644473 P.Liu, H.Cheng, T.M.Roberts, and J.J.Zhao (2009).
Targeting the phosphoinositide 3-kinase pathway in cancer.
  Nat Rev Drug Discov, 8, 627-644.  
  20622997 Q.Liu, C.Thoreen, J.Wang, D.Sabatini, and N.S.Gray (2009).
mTOR Mediated Anti-Cancer Drug Discovery.
  Drug Discov Today Ther Strateg, 6, 47-55.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
19465931 T.Okuzumi, D.Fiedler, C.Zhang, D.C.Gray, B.Aizenstein, R.Hoffman, and K.M.Shokat (2009).
Inhibitor hijacking of Akt activation.
  Nat Chem Biol, 5, 484-493.  
  19902965 T.W.Sturgill, and M.N.Hall (2009).
Activating mutations in TOR are in similar structures as oncogenic mutations in PI3KCalpha.
  ACS Chem Biol, 4, 999.  
19663506 Y.Wang, A.F.Monzingo, S.Hu, T.H.Schaller, J.D.Robertus, and W.Fast (2009).
Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide.
  Biochemistry, 48, 8624-8635.
PDB codes: 3i2e 3i4a
18936744 B.Bilanges, N.Torbett, and B.Vanhaesebroeck (2008).
Killing two kinase families with one stone.
  Nat Chem Biol, 4, 648-649.  
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 codes are shown on the right.