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PDBsum entry 3g45

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
3g45
Jmol PyMol
Contents
Protein chains
371 a.a. *
Ligands
988 ×2
Metals
_ZN ×2
_MG ×2
Waters ×100
* Residue conservation analysis
PDB id:
3g45
Name: Hydrolase
Title: Crystal structure of human phosphodiesterase 4b with regulatory domain and d155988
Structure: Camp-specific 3',5'-cyclic phosphodiesterase 4b. Chain: a, b. Fragment: s241 cloop, residues 241-289 and 305-659. Synonym: dpde4, pde32. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4b, dpde4. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
2.63Å     R-factor:   0.181     R-free:   0.233
Authors: B.L.Staker
Key ref:
A.B.Burgin et al. (2010). Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol, 28, 63-70. PubMed id: 20037581 DOI: 10.1038/nbt.1598
Date:
03-Feb-09     Release date:   19-Jan-10    
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.
371 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: 10.1038/nbt.1598 Nat Biotechnol 28:63-70 (2010)
PubMed id: 20037581  
 
 
Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
A.B.Burgin, O.T.Magnusson, J.Singh, P.Witte, B.L.Staker, J.M.Bjornsson, M.Thorsteinsdottir, S.Hrafnsdottir, T.Hagen, A.S.Kiselyov, L.J.Stewart, M.E.Gurney.
 
  ABSTRACT  
 
Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.
 
  Selected figure(s)  
 
Figure 2.
(a) A surface representation of the PDE4D catalytic domain (gray) bound with RS25344 (F[o]-F[c] omit maps in magenta) interacting with UCR2 (green) (PDB ID: 3G4G). (b) Schematic representation of RS25344 interacting with catalytic domain residues (Met439, Phe506, Phe538, Ile502, Gln535) and UCR2 (Phe196). (c) A surface representation of the PDE4B catalytic domain (gray) bound with PMNPQ (F[o]-F[c] omit maps in magenta) interacting with UCR2 (green) (PDB ID: 3G45). (d) Schematic representation of PMNPQ interacting with catalytic domain residues (Met519, Phe586, Phe618, Ile582, Gln615) and UCR2 (Tyr274). (e) Key hydrophobic interactions between the UCR2 domain (PDE4D(PDB ID: 3G4G)) and the catalytic domain. The UCR2 helix is surface rendered, and key residues are highlighted in green. The catalytic domain is surface rendered, and key residues are highlighted in blue. (f) The UCR2 helix is shown without surface rendering. Hydrophilic residues oriented toward solvent are labeled. RS25344 is not illustrated in order to simplify visualization of the interactions between UCR2 and the catalytic domain.
Figure 4.
Key elements of the pharmacophore include a planar scaffold providing a hydrogen bond acceptor, a linker and two aromatic substituents that create a clamp to hold UCR2 in the closed conformation across the active site. F and P signify compounds with “full” or “partial” inhibition kinetic behavior. (a) Scaffolds providing a hydrogen-bond acceptor to Gln535. (b) Aromatic Ar[1] substituents providing a part of the UCR2 clamp. (c) Aromatic Ar[2] substituents providing a part of the UCR2 clamp. (d) Co-crystal structure of a representative methoxyphenyl allosteric modulator (D159153) bound to PDE4D showing the UCR2 helix in the closed conformation. The regulatory helix is shown as a ribbon (green), the Fo-Fc omit map for the ligand is highlighted in magenta, and the active site surface is rendered in gray with key residues colored cyan. (e) Binding mode of D159153 to PDE4D indicating critical interactions.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Biotechnol (2010, 28, 63-70) copyright 2010.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21323643 K.F.MacKenzie, D.A.Wallace, E.V.Hill, D.F.Anthony, D.J.Henderson, D.M.Houslay, J.S.Arthur, G.S.Baillie, and M.D.Houslay (2011).
Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation.
  Biochem J, 435, 755-769.  
21327879 L.X.Li, Y.F.Cheng, H.B.Lin, C.Wang, J.P.Xu, and H.T.Zhang (2011).
Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats.
  Metab Brain Dis, 26, 37-47.  
21530250 R.W.Allcock, H.Blakli, Z.Jiang, K.A.Johnston, K.M.Morgan, G.M.Rosair, K.Iwase, Y.Kohno, and D.R.Adams (2011).
Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast.
  Bioorg Med Chem Lett, 21, 3307-3312.  
21437195 W.C.Ko, L.H.Lin, H.Y.Shen, C.Y.Lai, C.M.Chen, and C.H.Shih (2011).
Biochanin a, a phytoestrogenic isoflavone with selective inhibition of phosphodiesterase 4, suppresses ovalbumin-induced airway hyperresponsiveness.
  Evid Based Complement Alternat Med, 2011, 635058.  
21296667 X.D.Wang, Y.Chen, M.Wolf, K.V.Wagner, C.Liebl, S.H.Scharf, D.Harbich, B.Mayer, W.Wurst, F.Holsboer, J.M.Deussing, T.Z.Baram, M.B.Müller, and M.V.Schmidt (2011).
Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling.
  Neurobiol Dis, 42, 300-310.  
20701803 K.R.Johnson, J.Nicodemus-Johnson, and R.S.Danziger (2010).
An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing.
  BMC Evol Biol, 10, 247.  
20062038 M.D.Houslay, and D.R.Adams (2010).
Putting the lid on phosphodiesterase 4.
  Nat Biotechnol, 28, 38-40.  
20397815 N.J.Gross, M.A.Giembycz, and S.I.Rennard (2010).
Treatment of chronic obstructive pulmonary disease with roflumilast, a new phosphodiesterase 4 inhibitor.
  COPD, 7, 141-153.  
20196770 X.Li, S.Vadrevu, A.Dunlop, J.Day, N.Advant, J.Troeger, E.Klussmann, E.Jaffrey, R.T.Hay, D.R.Adams, M.D.Houslay, and G.S.Baillie (2010).
Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK.
  Biochem J, 428, 55-65.  
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.

 

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