PDBsum entry 1udu

Hydrolase

PDB id: 1udu

Contents

Protein chain

313 a.a. *

Ligands

CIA ×2

Metals

_ZN ×2

_MG ×2

* Residue conservation analysis

PDB id:

1udu

Name:

Hydrolase

Title:

Crystal structure of human phosphodiesterase 5 complexed with tadalafil(cialis)

Structure:

Cgmp-specific 3',5'-cyclic phosphodiesterase. Chain: a, b. Fragment: catalytic domain. Synonym: phosphodiesterase 5. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.83Å R-factor: 0.263 R-free: 0.374

Authors:

B.-J.Sung,J.I.Lee,Y.-S.Heo,J.H.Kim,J.Moon,J.M.Yoon,Y.-L.Hyun,E.Kim, S.J.Eum,T.G.Lee,J.M.Cho,S.-Y.Park,J.-O.Lee,Y.H.Jeon,K.Y.Hwang,S.Ro

Key ref:

B.J.Sung et al. (2003). Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature, 425, 98. PubMed id: 12955149 DOI: 10.1038/nature01914

Date:

06-May-03 Release date: 11-May-04

Protein chains

O76074  (PDE5A_HUMAN) -  cGMP-specific 3',5'-cyclic phosphodiesterase from Homo sapiens

Seq: 875 a.a.

Struc: 313 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.35 - 3',5'-cyclic-GMP phosphodiesterase.
• Reaction: 3',5'-cyclic GMP + H2O = GMP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/nature01914

Nature 425:98 (2003)

PubMed id: 12955149

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.

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, J.M.Cho.

ABSTRACT

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.

Selected figure(s)

Figure 2.
Figure 2: Stereo view of the active site of the PDE5 -sildenafil complex. Sildenafil is shown as a stick model with carbon atoms coloured yellow. Metal- and inhibitor-binding residues of PDE5 are shown as stick models with carbon atoms coloured white. The zinc (the bigger CPK model) and magnesium ions are shown in orange and green, respectively. The amide moiety of the pyrazolopyrimidinone group of sildenafil forms a bidentate hydrogen bond with the -amide group of Gln 817, which is well ordered by a hydrogen bond relay involving Gln 817 to Gln 775, Gln 775 to Ala 767 and Gln 775 to Trp 853. The model orientation is the same as in Fig. 1a.

Figure 3.
Figure 3: Comparison of PDE5 and PDE4 active sites. a, Superimposed C traces of PDE5 (red) and PDE4 (blue)9 showing the difference between the two folds at the active site. Residues 304 -325 of PDE5 and 660 -680 of PDE4D are shown with deeper colours to emphasize the differences in this region. The stick model of sildenafil is shown in yellow and that of zardaverine^9 in green. b, Surface representation of active site pocket of PDE5. The molecular surface is coloured according to electrostatic potential (negative and positive in red and blue, respectively). Residues that form the active site pocket are shown in green. The bound sildenafil in PDE5 is shown as a stick model.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2003, 425, 98-0) copyright 2003.

Figures were selected by an automated process.