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PDBsum entry 3dbs
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Transferase PDB id
3dbs

 

 

 

 

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Contents
Protein chain
841 a.a. *
Ligands
GD9
* Residue conservation analysis
PDB id:
3dbs
Name: Transferase
Title: Structure of pi3k gamma in complex with gdc0941
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform. Chain: a. Fragment: pi3k gamma, unp residues 143-1102. Synonym: pi3-kinase p110 subunit gamma, ptdins-3-kinase subunit p110, pi3k, pi3kgamma, p120-pi3k. Ec: 2.7.1.153
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
2.80Å     R-factor:   0.221     R-free:   0.262
Authors: C.Wiesmann,M.Ultsch
Key ref: A.J.Folkes et al. (2008). The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . J Med Chem, 51, 5522-5532. PubMed id: 18754654
Date:
02-Jun-08     Release date:   17-Jun-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P48736  (PK3CG_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1102 a.a.
841 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.2.7.11.1  - non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
   Enzyme class 3: E.C.2.7.1.137  - phosphatidylinositol 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H+
1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol)
 + ATP
 = 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate)
 + ADP
 + H(+)
   Enzyme class 4: E.C.2.7.1.153  - phosphatidylinositol-4,5-bisphosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate) + ADP + H+
1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate)
 + ATP
 = 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate)
 + ADP
 + H(+)
   Enzyme class 5: E.C.2.7.1.154  - phosphatidylinositol-4-phosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + ADP + H+
1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate)
 + ATP
 = 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate)
 + ADP
 + H(+)
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

 

 
    reference    
 
 
J Med Chem 51:5522-5532 (2008)
PubMed id: 18754654  
 
 
The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .
A.J.Folkes, K.Ahmadi, W.K.Alderton, S.Alix, S.J.Baker, G.Box, I.S.Chuckowree, P.A.Clarke, P.Depledge, S.A.Eccles, L.S.Friedman, A.Hayes, T.C.Hancox, A.Kugendradas, L.Lensun, P.Moore, A.G.Olivero, J.Pang, S.Patel, G.H.Pergl-Wilson, F.I.Raynaud, A.Robson, N.Saghir, L.Salphati, S.Sohal, M.H.Ultsch, M.Valenti, H.J.Wallweber, N.C.Wan, C.Wiesmann, P.Workman, A.Zhyvoloup, M.J.Zvelebil, S.J.Shuttleworth.
 
  ABSTRACT  
 
Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21224070 C.Couderc, G.Poncet, K.Villaume, M.Blanc, N.Gadot, T.Walter, F.Lepinasse, V.Hervieu, M.Cordier-Bussat, J.Y.Scoazec, and C.Roche (2011).
Targeting the PI3K/mTOR pathway in murine endocrine cell lines: in vitro and in vivo effects on tumor cell growth.
  Am J Pathol, 178, 336-344.  
21395485 D.W.Bowles, and A.Jimeno (2011).
New phosphatidylinositol 3-kinase inhibitors for cancer.
  Expert Opin Investig Drugs, 20, 507-518.  
21360822 J.A.Pinson, O.Schmidt-Kittler, J.Zhu, I.G.Jennings, K.W.Kinzler, B.Vogelstein, D.K.Chalmers, and P.E.Thompson (2011).
Thiazolidinedione-Based PI3Kα Inhibitors: An Analysis of Biochemical and Virtual Screening Methods.
  ChemMedChem, 6, 514-522.  
21407213 J.M.García-Martínez, S.Wullschleger, G.Preston, S.Guichard, S.Fleming, D.R.Alessi, and S.L.Duce (2011).
Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice.
  Br J Cancer, 104, 1116-1125.  
21253554 R.Conyers, S.Young, and D.M.Thomas (2011).
Liposarcoma: molecular genetics and therapeutics.
  Sarcoma, 2011, 483154.  
21362552 X.Zhang, O.Vadas, O.Perisic, K.E.Anderson, J.Clark, P.T.Hawkins, L.R.Stephens, and R.L.Williams (2011).
Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism.
  Mol Cell, 41, 567-578.
PDB code: 2y3a
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
19713247 B.Markman, F.Atzori, J.Pérez-García, J.Tabernero, and J.Baselga (2010).
Status of PI3K inhibition and biomarker development in cancer therapeutics.
  Ann Oncol, 21, 683-691.  
20823581 D.Kong, K.Yamazaki, and T.Yamori (2010).
Discovery of phosphatidylinositol 3-kinase inhibitory compounds from the Screening Committee of Anticancer Drugs (SCADS) library.
  Biol Pharm Bull, 33, 1600-1604.  
20729870 D.X.Kong, and T.Yamori (2010).
ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system.
  Acta Pharmacol Sin, 31, 1189-1197.  
20027191 F.J.Esteva, D.Yu, M.C.Hung, and G.N.Hortobagyi (2010).
Molecular predictors of response to trastuzumab and lapatinib in breast cancer.
  Nat Rev Clin Oncol, 7, 98.  
20826841 J.J.Wallin, J.Guan, W.W.Prior, K.A.Edgar, R.Kassees, D.Sampath, M.Belvin, and L.S.Friedman (2010).
Nuclear phospho-Akt increase predicts synergy of PI3K inhibition and doxorubicin in breast and ovarian cancer.
  Sci Transl Med, 2, 48ra66.  
20880397 M.K.Mansley, and S.M.Wilson (2010).
Effects of nominally selective inhibitors of the kinases PI3K, SGK1 and PKB on the insulin-dependent control of epithelial Na+ absorption.
  Br J Pharmacol, 161, 571-588.  
20609406 P.Workman, and I.Collins (2010).
Probing the probes: fitness factors for small molecule tools.
  Chem Biol, 17, 561-577.  
20081818 P.Workman, and R.L.van Montfort (2010).
PI(3) kinases: revealing the delta lady.
  Nat Chem Biol, 6, 82-83.  
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.  
20799872 S.Carvalho, and F.Schmitt (2010).
Potential role of PI3K inhibitors in the treatment of breast cancer.
  Future Oncol, 6, 1251-1263.  
  20953381 S.M.Ivison, M.A.Khan, N.R.Graham, L.A.Shobab, Y.Yao, A.Kifayet, L.M.Sly, and T.S.Steiner (2010).
The p110α and p110β isoforms of class I phosphatidylinositol 3-kinase are involved in toll-like receptor 5 signaling in epithelial cells.
  Mediators Inflamm, 2010, 0.  
20361045 Z.Ding, J.Liang, J.Li, Y.Lu, V.Ariyaratna, Z.Lu, M.A.Davies, J.K.Westwick, and G.B.Mills (2010).
Physical association of PDK1 with AKT1 is sufficient for pathway activation independent of membrane localization and phosphatidylinositol 3 kinase.
  PLoS One, 5, e9910.  
19584227 F.I.Raynaud, S.A.Eccles, S.Patel, S.Alix, G.Box, I.Chuckowree, A.Folkes, S.Gowan, A.De Haven Brandon, F.Di Stefano, A.Hayes, A.T.Henley, L.Lensun, G.Pergl-Wilson, A.Robson, N.Saghir, A.Zhyvoloup, E.McDonald, P.Sheldrake, S.Shuttleworth, M.Valenti, N.C.Wan, P.A.Clarke, and P.Workman (2009).
Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941.
  Mol Cancer Ther, 8, 1725-1738.  
19402821 J.M.García-Martínez, J.Moran, R.G.Clarke, A.Gray, S.C.Cosulich, C.M.Chresta, and D.R.Alessi (2009).
Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR).
  Biochem J, 421, 29-42.  
  19349352 K.T.Kuo, T.L.Mao, S.Jones, E.Veras, A.Ayhan, T.L.Wang, R.Glas, D.Slamon, V.E.Velculescu, R.J.Kuman, and I.e.M.Shih (2009).
Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma.
  Am J Pathol, 174, 1597-1601.  
19382889 M.K.Hancock, L.Kopp, and K.Bi (2009).
High-throughput screening compatible cell-based assay for interrogating activated notch signaling.
  Assay Drug Dev Technol, 7, 68-79.  
19805051 M.L.Sos, S.Fischer, R.Ullrich, M.Peifer, J.M.Heuckmann, M.Koker, S.Heynck, I.Stückrath, J.Weiss, F.Fischer, K.Michel, A.Goel, L.Regales, K.A.Politi, S.Perera, M.Getlik, L.C.Heukamp, S.Ansén, T.Zander, R.Beroukhim, H.Kashkar, K.M.Shokat, W.R.Sellers, D.Rauh, C.Orr, K.P.Hoeflich, L.Friedman, K.K.Wong, W.Pao, and R.K.Thomas (2009).
Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.
  Proc Natl Acad Sci U S A, 106, 18351-18356.  
  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.  
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.  
19411071 T.T.Junttila, R.W.Akita, K.Parsons, C.Fields, G.D.Lewis Phillips, L.S.Friedman, D.Sampath, and M.X.Sliwkowski (2009).
Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.
  Cancer Cell, 15, 429-440.  
19690175 W.Link, J.Oyarzabal, B.G.Serelde, M.I.Albarran, O.Rabal, A.Cebriá, P.Alfonso, J.Fominaya, O.Renner, S.Peregrina, D.Soilán, P.A.Ceballos, A.I.Hernández, M.Lorenzo, P.Pevarello, T.G.Granda, G.Kurz, A.Carnero, and J.R.Bischoff (2009).
Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases.
  J Biol Chem, 284, 28392-28400.  
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.

 

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