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PDBsum entry 1oyn
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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
1oyn

 

 

 

 

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Contents
Protein chains
334 a.a. *
Ligands
ROL ×4
Metals
_ZN ×8
Waters ×173
* Residue conservation analysis
PDB id:
1oyn
Name: Hydrolase
Title: Crystal structure of pde4d2 in complex with (r,s)-rolipram
Structure: Camp-specific phosphodiesterase pde4d2. Chain: a, b, c, d. Fragment: catalytic domain. Synonym: dpde3, pde43, pde4d2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4d2. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
2.00Å     R-factor:   0.233     R-free:   0.266
Authors: Q.Huai,H.Wang,Y.Sun,H.Y.Kim,Y.Liu,H.Ke
Key ref:
Q.Huai et al. (2003). Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure, 11, 865-873. PubMed id: 12842049 DOI: 10.1016/S0969-2126(03)00123-0
Date:
05-Apr-03     Release date:   15-Jul-03    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q08499  (PDE4D_HUMAN) -  3',5'-cyclic-AMP phosphodiesterase 4D from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		809 a.a.
334 a.a.
Key:    PfamA 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: 3',5'-cyclic AMP + H2O = AMP + H+
3',5'-cyclic AMP
 + H2O
 = AMP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1016/S0969-2126(03)00123-0 Structure 11:865-873 (2003)
PubMed id: 12842049  
 
 
Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity.
Q.Huai, H.Wang, Y.Sun, H.Y.Kim, Y.Liu, H.Ke.
 
  ABSTRACT  
 
Selective inhibitors against the 11 families of cyclic nucleotide phosphodiesterases (PDEs) are used to treat various human diseases. How the inhibitors selectively bind the conserved PDE catalytic domains is unknown. The crystal structures of the PDE4D2 catalytic domain in complex with (R)- or (R,S)-rolipram suggest that inhibitor selectivity is determined by the chemical nature of amino acids and subtle conformational changes of the binding pockets. The conformational states of Gln369 in PDE4D2 may play a key role in inhibitor recognition. The corresponding Y329S mutation in PDE7 may lead to loss of the hydrogen bonds between rolipram and Gln369 and is thus a possible reason explaining PDE7's insensitivity to rolipram inhibition. Docking of the PDE5 inhibitor sildenafil into the PDE4 catalytic pocket further helps understand inhibitor selectivity.
 
  Selected figure(s)  
 
Figure 6.
Figure 6. A Model for Insensitivity of PDE7 to Rolipram Inhibition(A) The hydrogen bonds (dotted lines) between Gln369 and rolipram in PDE4.(B) The correspondence of residues Ser373, Ser377, and Gln413 in PDE7A to Tyr329, Thr333, and Gln369 in PDE4D2 may lead Gln413 to adopt a new conformation to form a hydrogen bond with Ser377. As a result, Gln413 would not be capable of forming hydrogen bonds with rolipram. The orange sticks mark the side chain conformation of Gln369 in PDE4.
 
  The above figure is reprinted by permission from Cell Press: Structure (2003, 11, 865-873) copyright 2003.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20228279 M.A.Alaamery, A.R.Wyman, F.D.Ivey, C.Allain, D.Demirbas, L.Wang, O.Ceyhan, and C.S.Hoffman (2010).
New classes of PDE7 inhibitors identified by a fission yeast-based HTS.
  J Biomol Screen, 15, 359-367.  
20819076 R.J.Bird, G.S.Baillie, and S.J.Yarwood (2010).
Interaction with receptor for activated C-kinase 1 (RACK1) sensitizes the phosphodiesterase PDE4D5 towards hydrolysis of cAMP and activation by protein kinase C.
  Biochem J, 432, 207-216.  
19733234 A.Bhattacharya, A.Biswas, and P.K.Das (2009).
Role of a differentially expressed cAMP phosphodiesterase in regulating the induction of resistance against oxidative damage in Leishmania donovani.
  Free Radic Biol Med, 47, 1494-1506.  
19464886 A.P.Skoumbourdis, C.A.Leclair, E.Stefan, A.G.Turjanski, W.Maguire, S.A.Titus, R.Huang, D.S.Auld, J.Inglese, C.P.Austin, S.W.Michnick, M.Xia, and C.J.Thomas (2009).
Exploration and optimization of substituted triazolothiadiazines and triazolopyridazines as PDE4 inhibitors.
  Bioorg Med Chem Lett, 19, 3686-3692.  
19828435 J.Pandit, M.D.Forman, K.F.Fennell, K.S.Dillman, and F.S.Menniti (2009).
Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct.
  Proc Natl Acad Sci U S A, 106, 18225-18230.
PDB codes: 3ibj 3itm 3itu
18983167 H.Wang, Z.Yan, S.Yang, J.Cai, H.Robinson, and H.Ke (2008).
Kinetic and structural studies of phosphodiesterase-8A and implication on the inhibitor selectivity.
  Biochemistry, 47, 12760-12768.
PDB codes: 3ecm 3ecn
18757755 S.Liu, M.N.Mansour, K.S.Dillman, J.R.Perez, D.E.Danley, P.A.Aeed, S.P.Simons, P.K.Lemotte, and F.S.Menniti (2008).
Structural basis for the catalytic mechanism of human phosphodiesterase 9.
  Proc Natl Acad Sci U S A, 105, 13309-13314.
PDB codes: 3dy8 3dyl 3dyn 3dyq 3dys
19049349 S.Zheng, G.Kaur, H.Wang, M.Li, M.Macnaughtan, X.Yang, S.Reid, J.Prestegard, B.Wang, and H.Ke (2008).
Design, synthesis, and structure-activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors.
  J Med Chem, 51, 7673-7688.  
18044094 D.Wang, and X.Cui (2006).
Evaluation of PDE4 inhibition for COPD.
  Int J Chron Obstruct Pulmon Dis, 1, 373-379.  
16843671 F.G.Oliveira, C.M.Sant'Anna, E.R.Caffarena, L.E.Dardenne, and E.J.Barreiro (2006).
Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors.
  Bioorg Med Chem, 14, 6001-6011.  
16539372 Q.Huai, Y.Sun, H.Wang, D.Macdonald, R.Aspiotis, H.Robinson, Z.Huang, and H.Ke (2006).
Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase.
  J Med Chem, 49, 1867-1873.
PDB codes: 2fm0 2fm5
16407275 R.Zoraghi, J.D.Corbin, and S.H.Francis (2006).
Phosphodiesterase-5 Gln817 is critical for cGMP, vardenafil, or sildenafil affinity: its orientation impacts cGMP but not cAMP affinity.
  J Biol Chem, 281, 5553-5558.  
15685167 G.L.Card, L.Blasdel, B.P.England, C.Zhang, Y.Suzuki, S.Gillette, D.Fong, P.N.Ibrahim, D.R.Artis, G.Bollag, M.V.Milburn, S.H.Kim, J.Schlessinger, and K.Y.Zhang (2005).
A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design.
  Nat Biotechnol, 23, 201-207.
PDB codes: 1y2b 1y2c 1y2d 1y2e 1y2h 1y2j 1y2k
15994308 H.Wang, Y.Liu, Y.Chen, H.Robinson, and H.Ke (2005).
Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7.
  J Biol Chem, 280, 30949-30955.
PDB code: 1zkl
16300476 K.Y.Zhang, P.N.Ibrahim, S.Gillette, and G.Bollag (2005).
Phosphodiesterase-4 as a potential drug target.
  Expert Opin Ther Targets, 9, 1283-1305.  
16257373 M.D.Houslay, P.Schafer, and K.Y.Zhang (2005).
Keynote review: phosphodiesterase-4 as a therapeutic target.
  Drug Discov Today, 10, 1503-1519.  
15677448 R.Zoraghi, E.P.Bessay, J.D.Corbin, and S.H.Francis (2005).
Structural and functional features in human PDE5A1 regulatory domain that provide for allosteric cGMP binding, dimerization, and regulation.
  J Biol Chem, 280, 12051-12063.  
15576036 G.L.Card, B.P.England, Y.Suzuki, D.Fong, B.Powell, B.Lee, C.Luu, M.Tabrizizad, S.Gillette, P.N.Ibrahim, D.R.Artis, G.Bollag, M.V.Milburn, S.H.Kim, J.Schlessinger, and K.Y.Zhang (2004).
Structural basis for the activity of drugs that inhibit phosphodiesterases.
  Structure, 12, 2233-2247.
PDB codes: 1xlx 1xlz 1xm4 1xm6 1xmu 1xmy 1xn0 1xom 1xon 1xoq 1xor 1xos 1xot 1xoz 1xp0
15260978 K.Y.Zhang, G.L.Card, Y.Suzuki, D.R.Artis, D.Fong, S.Gillette, D.Hsieh, J.Neiman, B.L.West, C.Zhang, M.V.Milburn, S.H.Kim, J.Schlessinger, and G.Bollag (2004).
A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases.
  Mol Cell, 15, 279-286.
PDB codes: 1t9r 1t9s 1taz 1tb5 1tb7 1tbb 1tbf
15332080 M.Conti (2004).
A view into the catalytic pocket of cyclic nucleotide phosphodiesterases.
  Nat Struct Mol Biol, 11, 809-810.  
14668322 Q.Huai, Y.Liu, S.H.Francis, J.D.Corbin, and H.Ke (2004).
Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity.
  J Biol Chem, 279, 13095-13101.
PDB codes: 1rko 1rkp 1zkn
14728691 S.Kunz, T.Kloeckner, L.O.Essen, T.Seebeck, and M.Boshart (2004).
TbPDE1, a novel class I phosphodiesterase of Trypanosoma brucei.
  Eur J Biochem, 271, 637-647.  
15066282 T.Hogg, U.Mechold, H.Malke, M.Cashel, and R.Hilgenfeld (2004).
Conformational antagonism between opposing active sites in a bifunctional RelA/SpoT homolog modulates (p)ppGpp metabolism during the stringent response [corrected].
  Cell, 117, 57-68.
PDB code: 1vj7
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.

 

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