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Hydrolase PDB id
1f0j
Jmol
Contents
Protein chains
351 a.a. *
Ligands
ARS ×5
Metals
_ZN ×2
_MG ×2
Waters ×755
* Residue conservation analysis
PDB id:
1f0j
Name: Hydrolase
Title: Catalytic domain of human phosphodiesterase 4b2b
Structure: Phosphodiesterase 4b. Chain: a, b. Fragment: catalytic domain. Synonym: pde4b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: monocyte. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469. Expression_system_cell_line: trichoplusia ni
Biol. unit: Dimer (from PQS)
Resolution:
1.77Å     R-factor:   0.204     R-free:   0.223
Authors: R.X.Xu,A.M.Hassell,D.Vanderwall,M.H.Lambert,W.D.Holmes, M.A.Luther,W.J.Rocque,M.V.Milburn,Y.Zhao,H.Ke,R.T.Nolte
Key ref:
R.X.Xu et al. (2000). Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science, 288, 1822-1825. PubMed id: 10846163 DOI: 10.1126/science.288.5472.1822
Date:
16-May-00     Release date:   26-Jul-00    
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.
351 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: Nucleoside 3',5'-cyclic phosphate + H2O = nucleoside 5'-phosphate
Nucleoside 3',5'-cyclic phosphate
 + H(2)O
 = nucleoside 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     catalytic activity     2 terms  

 

 
    Added reference    
 
 
DOI no: 10.1126/science.288.5472.1822 Science 288:1822-1825 (2000)
PubMed id: 10846163  
 
 
Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity.
R.X.Xu, A.M.Hassell, D.Vanderwall, M.H.Lambert, W.D.Holmes, M.A.Luther, W.J.Rocque, M.V.Milburn, Y.Zhao, H.Ke, R.T.Nolte.
 
  ABSTRACT  
 
Cyclic nucleotides are second messengers that are essential in vision, muscle contraction, neurotransmission, exocytosis, cell growth, and differentiation. These molecules are degraded by a family of enzymes known as phosphodiesterases, which serve a critical function by regulating the intracellular concentration of cyclic nucleotides. We have determined the three-dimensional structure of the catalytic domain of phosphodiesterase 4B2B to 1.77 angstrom resolution. The active site has been identified and contains a cluster of two metal atoms. The structure suggests the mechanism of action and basis for specificity and will provide a framework for structure-assisted drug design for members of the phosphodiesterase family.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Ribbon diagram of the secondary structure of the catalytic domain (residues 152 to 489) of PDE4B2B. ME1 is shown as a silver sphere (ME2 is behind H13 in this orientation). The NH[2]-terminal subdomain of the molecule (residues 152 to 274) is colored cyan, the middle subdomain green (residues 275 to 347), and the COOH-terminal subdomain is colored yellow (residues 348 to 489). 		Figure 4.
Fig. 4. Model of cAMP bound to PDE4. A molecular docking procedure was used to fit cAMP into the proposed active site (34). The preferred model is shown in which cAMP adopts the anti conformation with the adenine base inserted into a lipophilic pocket formed by Leu393, Pro396, Ile^410, Phe^414, and Phe^446. The cyclic phosphate group binds to ME1 and ME2, replacing the observed arsenate ion shown in Fig. 3. The 1-N and 6-NH[2] groups form hydrogen bonds with the side chain of Gln443, while the 7-N position forms a more distorted hydrogen bond with Asn395. The ribose ring binds loosely against Met347 and Leu393, with a hydrogen bond between His234 and the O3' oxygen, but with no obvious interaction to the O2', O4', and O5' atoms. Consistent with our model, an experimental synthetic cAMP analog study found that PDE4 makes important interactions with the 1-N, 6-NH[2], and 7-N positions, but not with the 2'-OH (35).
 
  The above figures are reprinted by permission from the AAAs: Science (2000, 288, 1822-1825) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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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).
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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.
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  19281073 D.M.Halpin (2008).
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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].
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15378407 Y.Adachi, J.Yoshida, Y.Kodera, A.Kato, Y.Yoshikawa, Y.Kojima, and H.Sakurai (2004).
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Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity.
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PDB codes: 1oym 1oyn 1q9m
11930017 A.Rascón, S.H.Soderling, J.B.Schaefer, and J.A.Beavo (2002).
Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei.
  Proc Natl Acad Sci U S A, 99, 4714-4719.  
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Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis.
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Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling.
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  12457773 D.Boassa, and A.J.Yool (2002).
A fascinating tail: cGMP activation of aquaporin-1 ion channels.
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12429831 M.E.Meima, R.M.Biondi, and P.Schaap (2002).
Identification of a novel type of cGMP phosphodiesterase that is defective in the chemotactic stmF mutants.
  Mol Biol Cell, 13, 3870-3877.  
11863434 S.H.Hung, K.S.Madhusoodanan, R.L.Boyd, J.L.Baldwin, R.F.Colman, and R.W.Colman (2002).
A nonhydrolyzable reactive cAMP analogue, (S(p))-8-[(4-bromo-2,3-dioxobutyl)thio]adenosine 3',5'-cyclic S-(methyl)monophosphorothioate, irreversibly inactivates human platelet cGMP-inhibited cAMP phosphodiesterase at micromolar concentrations.
  Biochemistry, 41, 2962-2969.  
12023945 S.J.MacKenzie, G.S.Baillie, I.McPhee, C.MacKenzie, R.Seamons, T.McSorley, J.Millen, M.B.Beard, G.van Heeke, and M.D.Houslay (2002).
Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in Upstream Conserved Region 1 (UCR1).
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11835503 W.Richter (2002).
3',5' Cyclic nucleotide phosphodiesterases class III: members, structure, and catalytic mechanism.
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11296225 K.L.Dodge, S.Khouangsathiene, M.S.Kapiloff, R.Mouton, E.V.Hill, M.D.Houslay, L.K.Langeberg, and J.D.Scott (2001).
mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module.
  EMBO J, 20, 1921-1930.  
11371644 N.A.Glavas, C.Ostenson, J.B.Schaefer, V.Vasta, and J.A.Beavo (2001).
T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3.
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11468344 W.Zhang, H.Ke, A.P.Tretiakova, B.Jameson, and R.W.Colman (2001).
Identification of overlapping but distinct cAMP and cGMP interaction sites with cyclic nucleotide phosphodiesterase 3A by site-directed mutagenesis and molecular modeling based on crystalline PDE4B.
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The next generation of PDE4 inhibitors.
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Histidine-607 and histidine-643 provide important interactions for metal support of catalysis in phosphodiesterase-5.
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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.