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PDBsum entry 2wxl
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Transferase PDB id
2wxl

 

 

 

 

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Contents
Protein chain
823 a.a. *
Ligands
ZS4
Waters ×258
* Residue conservation analysis
PDB id:
2wxl
Name: Transferase
Title: The crystal structure of the murine class ia pi 3-kinase p110delta in complex with zstk474.
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform. Chain: a. Fragment: residues 106-1044. Synonym: pi3-kinase p110 subunit delta, ptdins-3-kinase p110, p110delta, pi3k. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.
Resolution:
1.99Å     R-factor:   0.215     R-free:   0.254
Authors: A.Berndt,S.Miller,O.Williams,D.D.Lee,B.T.Houseman,J.I.Pacold, F.Gorrec,W.-C.Hon,Y.Liu,C.Rommel,P.Gaillard,T.Ruckle,M.K.Schwarz, K.M.Shokat,J.P.Shaw,R.L.Williams
Key ref:
A.Berndt et al. (2010). The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat Chem Biol, 6, 117-124. PubMed id: 20081827 DOI: 10.1038/nchembio.293
Date:
09-Nov-09     Release date:   12-Jan-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O35904  (PK3CD_MOUSE) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform from Mus musculus
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1043 a.a.
823 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.2.7.1.137  - phosphatidylinositol 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		1-Phosphatidyl-myo-inositol Metabolism
      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 3: 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(+)
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    
 
 
DOI no: 10.1038/nchembio.293 Nat Chem Biol 6:117-124 (2010)
PubMed id: 20081827  
 
 
The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
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, R.L.Williams.
 
  ABSTRACT  
 
Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
 
  Selected figure(s)  
 
Figure 3.
(a–e) Shown are the binding modes of DL06 (a), DL07 (b), ZSTK474 (c), AS5 (d) and GDC-0941 (e) in the active site of p110δ. Met752 is in its 'in' position for all these compounds. 		Figure 4.
(a) The highly p110δ-selective compound AS15 does not open the specificity pocket and makes extensive use of a hydrophobic patch between Trp760, Thr750 and Met752 adjacent to the adenine-binding pocket. The 2mF[o] – DF[c] contouring level is 1σ. (b) Chemical structures of AS15 and PIK-39. (c) Superposition of AS15 and PIK-39 to demonstrate their different modes of binding within the active site of p110δ.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2010, 6, 117-124) copyright 2010.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
21035483 L.Stephens, and P.Hawkins (2011).
Signalling via class IA PI3Ks.
  Adv Enzyme Regul, 51, 27-36.  
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
20154668 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 p110delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
  Nat Chem Biol, 6, 244.  
21030680 H.A.Dbouk, H.Pang, A.Fiser, and J.M.Backer (2010).
A biochemical mechanism for the oncogenic potential of the p110beta catalytic subunit of phosphoinositide 3-kinase.
  Proc Natl Acad Sci U S A, 107, 19897-19902.  
20189103 O.Williams, B.T.Houseman, E.J.Kunkel, B.Aizenstein, R.Hoffman, Z.A.Knight, and K.M.Shokat (2010).
Discovery of dual inhibitors of the immune cell PI3Ks p110delta and p110gamma: a prototype for new anti-inflammatory drugs.
  Chem Biol, 17, 123-134.  
20189098 P.E.Thompson, I.G.Jennings, and J.A.Pinson (2010).
Inflammatory twins from PI3K gang brought to justice?
  Chem Biol, 17, 101-102.  
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.  
20799872 S.Carvalho, and F.Schmitt (2010).
Potential role of PI3K inhibitors in the treatment of breast cancer.
  Future Oncol, 6, 1251-1263.  
20339072 S.Miller, B.Tavshanjian, A.Oleksy, O.Perisic, B.T.Houseman, K.M.Shokat, and R.L.Williams (2010).
Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34.
  Science, 327, 1638-1642.
PDB codes: 2x6f 2x6h 2x6i 2x6j 2x6k
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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