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Hydrolase PDB-id
1f0j
Biological unit* = asymmetric unit,
as shown
(*as deduced by PQS)
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Contents
Description
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References
PROCHECK
Protein chains
351 a.a. *
Ligands
ARS ×5
Metal ions
_ZN ×2
_MG ×2
Waters ×755

* Residue conservation analysis
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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

Biological unit:
Dimer (from PQS)

UniProt:
Chains A, B: Q07343 (PDE4B_HUMAN)
Pfam   ArchSchema ?
Seq:
Struc:
Seq:
Struc:
Seq: 736 a.a.
Struc: 351 a.a.*
Key:    PfamA domain
 Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme class:
E.C.3.1.4.17   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:
Nucleoside 3',5'-cyclic phosphate + H2O = nucleoside 5'-phosphate (see diagram below)

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
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Enzyme reaction for E.C.3.1.4.17


Nucleoside 3',5'-cyclic phosphate
+ H(2)O
=
nucleoside 5'-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site.

 
    Key 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
20062038 M.D.Houslay, and D.R.Adams (2010).
Putting the lid on phosphodiesterase 4.
  Nat Biotechnol, 28, 38-40.  
19887631 B.Chang, T.Grau, S.Dangel, R.Hurd, B.Jurklies, E.C.Sener, S.Andreasson, H.Dollfus, B.Baumann, S.Bolz, N.Artemyev, S.Kohl, J.Heckenlively, and B.Wissinger (2009).
A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene.
  Proc Natl Acad Sci U S A, 106, 19581-19586.  
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
  19281073 D.M.Halpin (2008).
ABCD of the phosphodiesterase family: interaction and differential activity in COPD.
  Int J Chron Obstruct Pulmon Dis, 3, 543-561.  
18660825 D.Spina (2008).
PDE4 inhibitors: current status.
  Br J Pharmacol, 155, 308-315.  
18348140 R.Arya, S.Aslam, S.Gupta, R.S.Bora, L.Vijayakrishnan, P.Gulati, S.Naithani, S.Mukherjee, S.Dastidar, A.Bhattacharya, and K.S.Saini (2008).
Production and characterization of pharmacologically active recombinant human phosphodiesterase 4B in Dictyostelium discoideum.
  Biotechnol J, 3, 938-947.  
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
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
17637971 J.D.Ye, C.D.Barth, P.S.Anjaneyulu, T.Tuschl, and J.A.Piccirilli (2007).
Reactions of phosphate and phosphorothiolate diesters with nucleophiles: comparison of transition state structures.
  Org Biomol Chem, 5, 2491-2497.  
17376027 M.Conti, and J.Beavo (2007).
Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling.
  Annu Rev Biochem, 76, 481-511.  
16509757 G.Down, S.Siederer, S.Lim, and P.Daley-Yates (2006).
Clinical pharmacology of Cilomilast.
  Clin Pharmacokinet, 45, 217-233.  
17012379 P.M.Brown, T.T.Caradoc-Davies, J.M.Dickson, G.J.Cooper, K.M.Loomes, and E.N.Baker (2006).
Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism.
  Proc Natl Acad Sci U S A, 103, 15032-15037.
PDB code: 2huo
16287129 Q.Xu, R.Schwarzenbacher, D.McMullan, P.Abdubek, S.Agarwalla, E.Ambing, H.Axelrod, T.Biorac, J.M.Canaves, H.J.Chiu, A.M.Deacon, M.DiDonato, M.A.Elsliger, A.Godzik, C.Grittini, S.K.Grzechnik, J.Hale, E.Hampton, G.W.Han, J.Haugen, M.Hornsby, L.Jaroszewski, H.E.Klock, E.Koesema, A.Kreusch, P.Kuhn, S.A.Lesley, M.D.Miller, K.Moy, E.Nigoghossian, J.Paulsen, K.Quijano, R.Reyes, C.Rife, G.Spraggon, R.C.Stevens, H.van den Bedem, J.Velasquez, A.White, G.Wolf, K.O.Hodgson, J.Wooley, and I.A.Wilson (2006).
Crystal structure of virulence factor CJ0248 from Campylobacter jejuni at 2.25 A resolution reveals a new fold.
  Proteins, 62, 292-296.
PDB code: 1vqr
17172443 V.Vasta, M.Shimizu-Albergine, and J.A.Beavo (2006).
Modulation of Leydig cell function by cyclic nucleotide phosphodiesterase 8A.
  Proc Natl Acad Sci U S A, 103, 19925-19930.  
16912214 Y.Xiong, H.T.Lu, Y.Li, G.F.Yang, and C.G.Zhan (2006).
Characterization of a catalytic ligand bridging metal ions in phosphodiesterases 4 and 5 by molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations.
  Biophys J, 91, 1858-1867.  
15514991 A.Castro, M.J.Jerez, C.Gil, and A.Martinez (2005).
Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: advances in the development of specific phosphodiesterase inhibitors.
  Med Res Rev, 25, 229-244.  
15685201 A.Trifilieff, T.H.Keller, N.J.Press, T.Howe, P.Gedeck, D.Beer, and C.Walker (2005).
CGH2466, a combined adenosine receptor antagonist, p38 mitogen-activated protein kinase and phosphodiesterase type 4 inhibitor with potent in vitro and in vivo anti-inflammatory activities.
  Br J Pharmacol, 144, 1002-1010.  
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
15870731 J.A.Doudna, and J.R.Lorsch (2005).
Ribozyme catalysis: not different, just worse.
  Nat Struct Mol Biol, 12, 395-402.  
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.  
15955067 L.I.Castro, C.Hermsen, J.E.Schultz, and J.U.Linder (2005).
Adenylyl cyclase Rv0386 from Mycobacterium tuberculosis H37Rv uses a novel mode for substrate selection.
  FEBS J, 272, 3085-3092.  
15901640 V.Vasta, W.K.Sonnenburg, C.Yan, S.H.Soderling, M.Shimizu-Albergine, and J.A.Beavo (2005).
Identification of a new variant of PDE1A calmodulin-stimulated cyclic nucleotide phosphodiesterase expressed in mouse sperm.
  Biol Reprod, 73, 598-609.  
15332080 M.Conti (2004).
A view into the catalytic pocket of cyclic nucleotide phosphodiesterases.
  Nat Struct Mol Biol, 11, 809-810.  
15210993 Q.Huai, H.Wang, W.Zhang, R.W.Colman, H.Robinson, and H.Ke (2004).
Crystal structure of phosphodiesterase 9 shows orientation variation of inhibitor 3-isobutyl-1-methylxanthine binding.
  Proc Natl Acad Sci U S A, 101, 9624-9629.
PDB codes: 1tbm 2hd1
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.  
15378407 Y.Adachi, J.Yoshida, Y.Kodera, A.Kato, Y.Yoshikawa, Y.Kojima, and H.Sakurai (2004).
A new insulin-mimetic bis(allixinato)zinc(II) complex: structure-activity relationship of zinc(II) complexes.
  J Biol Inorg Chem, 9, 885-893.  
12955149 B.J.Sung, K.Y.Hwang, Y.H.Jeon, J.I.Lee, Y.S.Heo, J.H.Kim, J.Moon, J.M.Yoon, Y.L.Hyun, E.Kim, S.J.Eum, S.Y.Park, J.O.Lee, T.G.Lee, S.Ro, and J.M.Cho (2003).
Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.
  Nature, 425, 98.
PDB codes: 1udt 1udu 1uho
12552097 G.S.Baillie, A.Sood, I.McPhee, I.Gall, S.J.Perry, R.J.Lefkowitz, and M.D.Houslay (2003).
beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi.
  Proc Natl Acad Sci U S A, 100, 940-945.  
14585965 J.Arp, M.G.Kirchhof, M.L.Baroja, S.H.Nazarian, T.A.Chau, C.A.Strathdee, E.H.Ball, and J.Madrenas (2003).
Regulation of T-cell activation by phosphodiesterase 4B2 requires its dynamic redistribution during immunological synapse formation.
  Mol Cell Biol, 23, 8042-8057.  
12603329 M.J.Frame, R.Tate, D.R.Adams, K.M.Morgan, M.D.Houslay, P.Vandenabeele, and N.J.Pyne (2003).
Interaction of caspase-3 with the cyclic GMP binding cyclic GMP specific phosphodiesterase (PDE5a1).
  Eur J Biochem, 270, 962-970.  
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.  
  12370283 A.Robichaud, P.B.Stamatiou, S.L.Jin, N.Lachance, D.MacDonald, F.Laliberté, S.Liu, Z.Huang, M.Conti, and C.C.Chan (2002).
Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis.
  J Clin Invest, 110, 1045-1052.  
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).
  Br J Pharmacol, 136, 421-433.  
11835503 W.Richter (2002).
3',5' Cyclic nucleotide phosphodiesterases class III: members, structure, and catalytic mechanism.
  Proteins, 46, 278-286.  
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.
  Proc Natl Acad Sci U S A, 98, 6319-6324.  
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.
  Protein Sci, 10, 1481-1489.  
10924156 S.H.Francis, I.V.Turko, K.A.Grimes, and J.D.Corbin (2000).
Histidine-607 and histidine-643 provide important interactions for metal support of catalysis in phosphodiesterase-5.
  Biochemistry, 39, 9591-9596.  
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.