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PDBsum entry 3wd9

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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
3wd9
Jmol PyMol
Contents
Protein chains
345 a.a.
Ligands
QPC ×2
Metals
_CA ×2
_ZN ×2
Waters ×341
PDB id:
3wd9
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of phosphodiesterase 4b in complex with co
Structure: Camp-specific 3',5'-cyclic phosphodiesterase 4b. Chain: a, b. Fragment: unp residues 324-700. Synonym: dpde4, pde32. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: dpde4, pde4b. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.50Å     R-factor:   0.183     R-free:   0.267
Authors: M.Takahashi,H.Hanzawa
Key ref: T.Goto et al. (2013). Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. Bioorg Med Chem, 21, 7025-7037. PubMed id: 24094436 DOI: 10.1016/j.bmc.2013.09.013
Date:
11-Jun-13     Release date:   23-Oct-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q07343  (PDE4B_HUMAN) -  cAMP-specific 3',5'-cyclic phosphodiesterase 4B
Seq:
Struc:
 
Seq:
Struc:
736 a.a.
345 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.1.4.53  - 3',5'-cyclic-AMP phosphodiesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Adenosine 3',5'-cyclic phosphate + H2O = adenosine 5'-phosphate
Adenosine 3',5'-cyclic phosphate
+ H(2)O
= adenosine 5'-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     signal transduction   1 term 
  Biochemical function     phosphoric diester hydrolase activity     2 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/j.bmc.2013.09.013 Bioorg Med Chem 21:7025-7037 (2013)
PubMed id: 24094436  
 
 
Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.
T.Goto, A.Shiina, T.Yoshino, K.Mizukami, K.Hirahara, O.Suzuki, Y.Sogawa, T.Takahashi, T.Mikkaichi, N.Nakao, M.Takahashi, M.Hasegawa, S.Sasaki.
 
  ABSTRACT  
 
5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0mg/kg, i.t.).
 

 

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