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PDBsum entry 2og8

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2og8
Jmol
Contents
Protein chains
246 a.a. *
Ligands
1N8 ×2
Waters ×209
* Residue conservation analysis
PDB id:
2og8
Name: Transferase
Title: Crystal structure of aminoquinazoline 36 bound to lck
Structure: Proto-oncogene tyrosine-protein kinase lck. Chain: a, b. Fragment: lck kinase domain, residues 236-498. Synonym: p56-lck, lymphocyte cell-specific protein- tyrosine kinase, lsk, t cell- specific protein-tyrosine kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: lck. Expressed in: insect cell.
Resolution:
2.30Å     R-factor:   0.247     R-free:   0.300
Authors: X.Huang
Key ref: E.F.DiMauro et al. (2006). Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity. J Med Chem, 49, 5671-5686. PubMed id: 16970394 DOI: 10.1021/jm0605482
Date:
05-Jan-07     Release date:   27-Feb-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P06239  (LCK_HUMAN) -  Tyrosine-protein kinase Lck
Seq:
Struc:
509 a.a.
246 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.2  - Non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     regulation of signal transduction   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm0605482 J Med Chem 49:5671-5686 (2006)
PubMed id: 16970394  
 
 
Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.
E.F.DiMauro, J.Newcomb, J.J.Nunes, J.E.Bemis, C.Boucher, J.L.Buchanan, W.H.Buckner, V.J.Cee, L.Chai, H.L.Deak, L.F.Epstein, T.Faust, P.Gallant, S.D.Geuns-Meyer, A.Gore, Y.Gu, B.Henkle, B.L.Hodous, F.Hsieh, X.Huang, J.L.Kim, J.H.Lee, M.W.Martin, C.E.Masse, D.C.McGowan, D.Metz, D.Mohn, K.A.Morgenstern, A.Oliveira-dos-Santos, V.F.Patel, D.Powers, P.E.Rose, S.Schneider, S.A.Tomlinson, Y.Y.Tudor, S.M.Turci, A.A.Welcher, R.D.White, H.Zhao, L.Zhu, X.Zhu.
 
  ABSTRACT  
 
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20189109 P.Ranjitkar, A.M.Brock, and D.J.Maly (2010).
Affinity reagents that target a specific inactive form of protein kinases.
  Chem Biol, 17, 195-206.  
  18568424 S.S.Bhagwat (2009).
Kinase inhibitors for the treatment of inflammatory and autoimmune disorders.
  Purinergic Signal, 5, 107-115.  
18727154 V.M.Anisimov, and V.L.Bugaenko (2009).
QM/QM docking method based on the variational finite localized molecular orbital approximation.
  J Comput Chem, 30, 784-798.  
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.  
18940662 A.C.Dar, M.S.Lopez, and K.M.Shokat (2008).
Small molecule recognition of c-Src via the Imatinib-binding conformation.
  Chem Biol, 15, 1015-1022.
PDB codes: 3el7 3el8
  18300054 J.Won, and G.H.Lee (2008).
T-cell-targeted signaling inhibitors.
  Int Rev Immunol, 27, 19-41.  
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.