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PDBsum entry 1z1l
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Hydrolase PDB id
1z1l

 

 

 

 

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Contents
Protein chain
338 a.a. *
Ligands
PO4
Metals
_ZN
_MG
Waters ×272
* Residue conservation analysis
PDB id:
1z1l
Name: Hydrolase
Title: The crystal structure of the phosphodiesterase 2a catalytic domain
Structure: Cgmp-dependent 3',5'-cyclic phosphodiesterase. Chain: a. Fragment: catalytic domain, residues 578-919. Synonym: cyclic gmp stimulated phosphodiesterase, cgs-pde, cgspde. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pde2a. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
1.70Å     R-factor:   0.209     R-free:   0.237
Authors: Y.H.Ding,D.Kohls,C.Low
Key ref:
A.Iffland et al. (2005). Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry, 44, 8312-8325. PubMed id: 15938621 DOI: 10.1021/bi047313h
Date:
04-Mar-05     Release date:   21-Jun-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O00408  (PDE2A_HUMAN) -  cGMP-dependent 3',5'-cyclic phosphodiesterase from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		941 a.a.
338 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.1.4.17  - 3',5'-cyclic-nucleotide phosphodiesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-phosphate + H+
nucleoside 3',5'-cyclic phosphate
 + H2O
 = nucleoside 5'-phosphate
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1021/bi047313h Biochemistry 44:8312-8325 (2005)
PubMed id: 15938621  
 
 
Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system.
A.Iffland, D.Kohls, S.Low, J.Luan, Y.Zhang, M.Kothe, Q.Cao, A.V.Kamath, Y.H.Ding, T.Ellenberger.
 
  ABSTRACT  
 
Phosphodiesterases (PDEs) modulate signaling by cyclic nucleotides in diverse processes such as cardiac contractility, platelet aggregation, lipolysis, glycogenolysis, and smooth muscle contraction. Cyclic guanosine monophosphate (cGMP) stimulated human phosphodiesterase 2 (PDE2) is expressed mainly in brain and heart tissues. PDE2A is involved in the regulation of blood pressure and fluid homeostasis by the atrial natriuretic peptide (ANP), making PDE2-type enzymes important targets for drug discovery. The design of more potent and selective inhibitors of PDE2A for the treatment of heart disease would be greatly aided by the identification of active site residues in PDE2A that determine substrate and inhibitor selectivity. The identification of active site residues through traditional mutational studies involves the time-consuming and tedious purification of a large number of mutant proteins from overexpressing cells. Here we report an alternative approach to rapidly produce active site mutants of human PDE2A and identify their enzymatic properties using a wheat germ in vitro translation (IVT, also known as cell-free translation) system. We also present the crystal structure of the catalytic domain of human PDE2A determined at 1.7 A resolution, which provided a framework for the rational design of active site mutants. Using a rapid IVT approach for expression of human PDE2A mutants, we identified the roles of active site residues Asp811, Gln812, Ile826, and Tyr827 in inhibitor and substrate selectivity for PDE2A.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20520741 D.M.Leippe, K.Q.Zhao, K.Hsiao, and M.R.Slater (2010).
Cell-free expression of protein kinase a for rapid activity assays.
  Anal Chem Insights, 5, 25-36.  
19684253 A.Masood, Y.Huang, H.Hajjhussein, L.Xiao, H.Li, W.Wang, A.Hamza, C.G.Zhan, and J.M.O'Donnell (2009).
Anxiolytic effects of phosphodiesterase-2 inhibitors associated with increased cGMP signaling.
  J Pharmacol Exp Ther, 331, 690-699.  
19506089 D.T.Stephenson, T.M.Coskran, M.B.Wilhelms, W.O.Adamowicz, M.M.O'Donnell, K.B.Muravnick, F.S.Menniti, R.J.Kleiman, and D.Morton (2009).
Immunohistochemical localization of phosphodiesterase 2A in multiple mammalian species.
  J Histochem Cytochem, 57, 933-949.  
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
17716863 G.G.Holz, O.G.Chepurny, and F.Schwede (2008).
Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors.
  Cell Signal, 20, 10-20.  
18614542 S.E.Martinez, C.C.Heikaus, R.E.Klevit, and J.A.Beavo (2008).
The structure of the GAF A domain from phosphodiesterase 6C reveals determinants of cGMP binding, a conserved binding surface, and a large cGMP-dependent conformational change.
  J Biol Chem, 283, 25913-25919.
PDB code: 3dba
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
17582435 H.Wang, H.Robinson, and H.Ke (2007).
The molecular basis for different recognition of substrates by phosphodiesterase families 4 and 10.
  J Mol Biol, 371, 302-307.
PDB code: 2pw3
17389385 H.Wang, Y.Liu, J.Hou, M.Zheng, H.Robinson, and H.Ke (2007).
Structural insight into substrate specificity of phosphodiesterase 10.
  Proc Natl Acad Sci U S A, 104, 5782-5787.
PDB codes: 2oun 2oup 2ouq 2our 2ous 2ouu 2ouv 2ouy
17944832 H.Wang, Z.Yan, J.Geng, S.Kunz, T.Seebeck, and H.Ke (2007).
Crystal structure of the Leishmania major phosphodiesterase LmjPDEB1 and insight into the design of the parasite-selective inhibitors.
  Mol Microbiol, 66, 1029-1038.
PDB code: 2r8q
17329248 S.K.de Oliveira, M.Hoffmeister, S.Gambaryan, W.Müller-Esterl, J.A.Guimaraes, and A.P.Smolenski (2007).
Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor.
  J Biol Chem, 282, 13656-13663.  
16735511 H.Wang, Y.Liu, Q.Huai, J.Cai, R.Zoraghi, S.H.Francis, J.D.Corbin, H.Robinson, Z.Xin, G.Lin, and H.Ke (2006).
Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development.
  J Biol Chem, 281, 21469-21479.
PDB codes: 2h40 2h42 2h44
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
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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