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PDBsum entry 3dpk

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protein ligands links
Transferase PDB id
3dpk
Jmol
Contents
Protein chain
279 a.a. *
Ligands
SO4 ×3
8C5
Waters ×123
* Residue conservation analysis
PDB id:
3dpk
Name: Transferase
Title: Cfms tyrosine kinase in complex with a pyridopyrimidinone inhibitor
Structure: Macrophage colony-stimulating factor 1 receptor. Chain: a. Fragment: kinase domain. Synonym: csf-1-r, fms proto-oncogene, c-fms, cd115 antigen, fgfr-1, bfgf-r, fms-like tyrosine kinase 2, c-fgr, cd331 antige. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: csf1r, fms, fgfr1, fgfbr, flg, flt2. Expressed in: spodoptera frugiperda
Resolution:
1.95Å     R-factor:   0.192     R-free:   0.244
Authors: C.Schubert
Key ref: H.Huang et al. (2009). Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors. J Med Chem, 52, 1081-1099. PubMed id: 19193011 DOI: 10.1021/jm801406h
Date:
08-Jul-08     Release date:   17-Feb-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P07333  (CSF1R_HUMAN) -  Macrophage colony-stimulating factor 1 receptor
Seq:
Struc:
 
Seq:
Struc:
972 a.a.
279 a.a.*
Protein chain
Pfam   ArchSchema ?
P11362  (FGFR1_HUMAN) -  Fibroblast growth factor receptor 1
Seq:
Struc:
 
Seq:
Struc:
822 a.a.
279 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 135 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.1  - Receptor 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!
  Cellular component     membrane   1 term 
  Biological process     transmembrane receptor protein tyrosine kinase signaling pathway   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm801406h J Med Chem 52:1081-1099 (2009)
PubMed id: 19193011  
 
 
Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors.
H.Huang, D.A.Hutta, J.M.Rinker, H.Hu, W.H.Parsons, C.Schubert, R.L.DesJarlais, C.S.Crysler, M.A.Chaikin, R.R.Donatelli, Y.Chen, D.Cheng, Z.Zhou, E.Yurkow, C.L.Manthey, M.R.Player.
 
  ABSTRACT  
 
A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21337528 M.Irfan, T.N.Glasnov, and C.O.Kappe (2011).
Heterogeneous catalytic hydrogenation reactions in continuous-flow reactors.
  ChemSusChem, 4, 300-316.  
21095574 L.M.Wodicka, P.Ciceri, M.I.Davis, J.P.Hunt, M.Floyd, S.Salerno, X.H.Hua, J.M.Ford, R.C.Armstrong, P.P.Zarrinkar, and D.K.Treiber (2010).
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
  Chem Biol, 17, 1241-1249.  
20925095 R.Csuk, and E.Prell (2010).
Difluorotetrahydropyridothiazinone: a selective β-galactosidase inhibitor.
  Arch Pharm (Weinheim), 343, 577-582.  
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