PDBsum entry 2h44

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Hydrolase PDB id
Protein chain
326 a.a. *
Waters ×231
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of pde5a1 in complex with icarisid ii
Structure: Cgmp-specific 3',5'-cyclic phosphodiesterase. Chain: a. Fragment: catalytic domain, residues 535-860. Synonym: cgb-pde, cgmp-binding cgmp-specific phosphodiesterase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pde5a, pde5. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
1.80Å     R-factor:   0.206     R-free:   0.233
Authors: H.Wang,H.Ke
Key ref:
H.Wang et al. (2006). Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development. J Biol Chem, 281, 21469-21479. PubMed id: 16735511 DOI: 10.1074/jbc.M512527200
23-May-06     Release date:   06-Jun-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O76074  (PDE5A_HUMAN) -  cGMP-specific 3',5'-cyclic phosphodiesterase
875 a.a.
326 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - 3',5'-cyclic-GMP phosphodiesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Guanosine 3',5'-cyclic phosphate + H2O = guanosine 5'-phosphate
Guanosine 3',5'-cyclic phosphate
+ H(2)O
= guanosine 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     3 terms  


    Added reference    
DOI no: 10.1074/jbc.M512527200 J Biol Chem 281:21469-21479 (2006)
PubMed id: 16735511  
Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development.
H.Wang, Y.Liu, Q.Huai, J.Cai, R.Zoraghi, S.H.Francis, J.D.Corbin, H.Robinson, Z.Xin, G.Lin, H.Ke.
Phosphodiesterase-5 (PDE5) is the target for sildenafil, vardenafil, and tadalafil, which are drugs for treatment of erectile dysfunction and pulmonary hypertension. We report here the crystal structures of a fully active catalytic domain of unliganded PDE5A1 and its complexes with sildenafil or icarisid II. These structures together with the PDE5A1-isobutyl-1-methylxanthine complex show that the H-loop (residues 660-683) at the active site of PDE5A1 has four different conformations and migrates 7-35A upon inhibitor binding. In addition, the conformation of sildenafil reported herein differs significantly from those in the previous structures of chimerically hybridized or almost inactive PDE5. Mutagenesis and kinetic analyses confirm that the H-loop is particularly important for substrate recognition and that invariant Gly(659), which immediately precedes the H-loop, is critical for optimal substrate affinity and catalytic activity.
  Selected figure(s)  
Figure 1.
FIGURE 1. Chemical structures of PDE5 inhibitors. The letters R[1]-R[3] label the main groups in sildenafil and icarisid II. In sildenafil, R[1] represents the pyrazolopyrimidinone group; R[2] is ethoxyphenyl, and R[3] is methylpiperazine. In icarisid II, R[1] represents the methoxyphenyl group; R[2] is oxychromone, and R[3] is rhamnose.
Figure 4.
FIGURE 4. Icarisid II binding. A, electron density for icarisid II bound to PDE5A1. The F[o] - F[c] map was calculated from the structure with omission of icarisid II and contoured at 3.0 . B, stereoview of interaction of icarisid II (gold sticks) with the PDE5A1 residues (salmon sticks) at the active site of PDE5A1. The dotted lines represent hydrogen bonds. C, superposition of icarisid II (gold sticks) and sildenafil (purple ball-sticks). Residues from PDE5A-sildenafil are shown in blue, and residues from the icarisid II complex are in green. The side chain of Gln^817 has the different conformations in the two structures.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 21469-21479) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20121115 H.Wang, X.Luo, M.Ye, J.Hou, H.Robinson, and H.Ke (2010).
Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis.
  J Med Chem, 53, 1726-1731.
PDB codes: 3k3e 3k3h
20698857 R.Jäger, F.Schwede, H.G.Genieser, D.Koesling, and M.Russwurm (2010).
Activation of PDE2 and PDE5 by specific GAF ligands: delayed activation of PDE5.
  Br J Pharmacol, 161, 1645-1660.  
19798052 B.Barren, L.Gakhar, H.Muradov, K.K.Boyd, S.Ramaswamy, and N.O.Artemyev (2009).
Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the gamma-subunit.
  EMBO J, 28, 3613-3622.
PDB codes: 3jwq 3jwr
19665054 J.D.Corbin, R.Zoraghi, and S.H.Francis (2009).
Allosteric-site and catalytic-site ligand effects on PDE5 functions are associated with distinct changes in physical form of the enzyme.
  Cell Signal, 21, 1768-1774.  
19641165 J.L.Weeks, J.D.Corbin, and S.H.Francis (2009).
Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and substrates or tadalafil and role of a critical Gln-869 hydrogen bond.
  J Pharmacol Exp Ther, 331, 133-141.  
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
18534985 C.C.Heikaus, J.R.Stout, M.R.Sekharan, C.M.Eakin, P.Rajagopal, P.S.Brzovic, J.A.Beavo, and R.E.Klevit (2008).
Solution structure of the cGMP binding GAF domain from phosphodiesterase 5: insights into nucleotide specificity, dimerization, and cGMP-dependent conformational change.
  J Biol Chem, 283, 22749-22759.
PDB code: 2k31
18346713 G.Chen, H.Wang, H.Robinson, J.Cai, Y.Wan, and H.Ke (2008).
An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies.
  Biochem Pharmacol, 75, 1717-1728.
PDB code: 3bjc
17959709 H.Wang, M.Ye, H.Robinson, S.H.Francis, and H.Ke (2008).
Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil.
  Mol Pharmacol, 73, 104-110.
PDB code: 3b2r
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
18827577 S.C.Bischoff (2008).
Quercetin: potentials in the prevention and therapy of disease.
  Curr Opin Clin Nutr Metab Care, 11, 733-740.  
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
18779324 X.J.Zhang, K.B.Cahill, A.Elfenbein, V.Y.Arshavsky, and R.H.Cote (2008).
Direct allosteric regulation between the GAF domain and catalytic domain of photoreceptor phosphodiesterase PDE6.
  J Biol Chem, 283, 29699-29705.  
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
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.