PDBsum entry 1xp0

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Hydrolase PDB id
Jmol PyMol
Protein chain
326 a.a. *
Waters ×156
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Catalytic domain of human phosphodiesterase 5a in complex wi vardenafil
Structure: Cgmp-specific 3',5'-cyclic phosphodiesterase. Chain: a. Fragment: catalytic domain of human phosphodiesterase 5a. Synonym: cgb-pde, cgmp-binding cgmp-specific phosphodiester pde5a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pde5a, pde5. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.79Å     R-factor:   0.194     R-free:   0.208
Authors: G.L.Card,B.P.England,Y.Suzuki,D.Fong,B.Powell,B.Lee,C.Luu, M.Tabrizizad,S.Gillette,P.N.Ibrahim,D.R.Artis,G.Bollag,M.V. S.-H.Kim,J.Schlessinger,K.Y.J.Zhang
Key ref:
G.L.Card et al. (2004). Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure, 12, 2233-2247. PubMed id: 15576036 DOI: 10.1016/j.str.2004.10.004
07-Oct-04     Release date:   14-Dec-04    
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
* PDB and UniProt seqs differ at 18 residue positions (black crosses)

 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     phosphoric diester hydrolase activity     2 terms  


    Added reference    
DOI no: 10.1016/j.str.2004.10.004 Structure 12:2233-2247 (2004)
PubMed id: 15576036  
Structural basis for the activity of drugs that inhibit phosphodiesterases.
G.L.Card, B.P.England, Y.Suzuki, D.Fong, B.Powell, B.Lee, C.Luu, M.Tabrizizad, S.Gillette, P.N.Ibrahim, D.R.Artis, G.Bollag, M.V.Milburn, S.H.Kim, J.Schlessinger, K.Y.Zhang.
Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.
  Selected figure(s)  
Figure 1.
Figure 1. Classification of the Active Site of PDEs(A) The active site of PDEs is divided into three pockets: the metal binding pocket (M) shown in blue, the purine-selective glutamine and hydrophobic clamp pocket (Q) shown in red (which is further divided into Q[1] and Q[2] subpockets), and the solvent-filled side pocket (S) shown in green. This color coding of the active site pocket is mapped on the surface of PDE4B in complex with cilomilast, which is shown as a stick model bound at the active site. The cocrystal structure of PDE4B in complex with cilomilast has also been used to display the surfaces in (B)-(D).(B) Same as (A), but a view of the PDE active site looking toward the S pocket. This view is a clockwise rotation of about 90 along the length of cilomilast from the view in Figure 1A. The subpockets that subdivide the Q pocket are also labeled: Q[1] is the small subpocket, and Q[2] is the large subpocket.(C) Same as (A), but a view of the PDE active site looking away from the S pocket. This view is a counterclockwise rotation of about 90 along the length of cilomilast from the view in Figure 1A. All the subpockets are labeled.(D) Residues lining the three active site pockets. The active site surface is semitransparent to reveal residues that make up the active site. The absolutely conserved residues in all PDEs are colored blue. Residues conserved in both cAMP- and cGMP-specific PDEs are colored green. The other variable residues are colored red.
  The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 2233-2247) copyright 2004.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21530250 R.W.Allcock, H.Blakli, Z.Jiang, K.A.Johnston, K.M.Morgan, G.M.Rosair, K.Iwase, Y.Kohno, and D.R.Adams (2011).
Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast.
  Bioorg Med Chem Lett, 21, 3307-3312.  
20037581 A.B.Burgin, O.T.Magnusson, J.Singh, P.Witte, B.L.Staker, J.M.Bjornsson, M.Thorsteinsdottir, S.Hrafnsdottir, T.Hagen, A.S.Kiselyov, L.J.Stewart, and M.E.Gurney (2010).
Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
  Nat Biotechnol, 28, 63-70.
PDB codes: 3g45 3g4g 3g4i 3g4k 3g4l 3g58 3iad
20839298 K.Murata, N.Nagata, I.Nakanishi, and K.Kitaura (2010).
SDOVS: a solvent dipole ordering-based method for virtual screening.
  J Comput Chem, 31, 2714-2722.  
  20689641 M.A.Giembycz, and S.K.Field (2010).
Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD.
  Drug Des Devel Ther, 4, 147-158.  
20633297 P.V.Mazin, M.S.Gelfand, A.A.Mironov, A.B.Rakhmaninova, A.R.Rubinov, R.B.Russell, and O.V.Kalinina (2010).
An automated stochastic approach to the identification of the protein specificity determinants and functional subfamilies.
  Algorithms Mol Biol, 5, 29.  
20625148 S.King-Keller, M.Li, A.Smith, S.Zheng, G.Kaur, X.Yang, B.Wang, and R.Docampo (2010).
Chemical validation of phosphodiesterase C as a chemotherapeutic target in Trypanosoma cruzi, the etiological agent of Chagas' disease.
  Antimicrob Agents Chemother, 54, 3738-3745.  
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).
Exploration and optimization of substituted triazolothiadiazines and triazolopyridazines as PDE4 inhibitors.
  Bioorg Med Chem Lett, 19, 3686-3692.  
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
19232106 Y.Sato, Y.Hashiguchi, and M.Nishida (2009).
Evolution of multiple phosphodiesterase isoforms in stickleback involved in cAMP signal transduction pathway.
  BMC Syst Biol, 3, 23.  
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
18660825 D.Spina (2008).
PDE4 inhibitors: current status.
  Br J Pharmacol, 155, 308-315.  
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
18447606 S.K.Field (2008).
Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma.
  Expert Opin Investig Drugs, 17, 811-818.  
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.  
18161687 Y.Xiong, H.T.Lu, and C.G.Zhan (2008).
Dynamic structures of phosphodiesterase-5 active site by combined molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations.
  J Comput Chem, 29, 1259-1267.  
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.  
  18268925 W.M.Brown (2007).
Treating COPD with PDE 4 inhibitors.
  Int J Chron Obstruct Pulmon Dis, 2, 517-533.  
16542053 A.Ghavami, W.D.Hirst, and T.J.Novak (2006).
Selective phosphodiesterase (PDE)-4 inhibitors: a novel approach to treating memory deficit?
  Drugs R D, 7, 63-71.  
16522215 A.Johner, S.Kunz, M.Linder, Y.Shakur, and T.Seebeck (2006).
Cyclic nucleotide specific phosphodiesterases of Leishmania major.
  BMC Microbiol, 6, 25.  
18044094 D.Wang, and X.Cui (2006).
Evaluation of PDE4 inhibition for COPD.
  Int J Chron Obstruct Pulmon Dis, 1, 373-379.  
16843671 F.G.Oliveira, C.M.Sant'Anna, E.R.Caffarena, L.E.Dardenne, and E.J.Barreiro (2006).
Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors.
  Bioorg Med Chem, 14, 6001-6011.  
16883304 F.S.Menniti, W.S.Faraci, and C.J.Schmidt (2006).
Phosphodiesterases in the CNS: targets for drug development.
  Nat Rev Drug Discov, 5, 660-670.  
16988956 H.Park, J.Lee, and S.Lee (2006).
Critical assessment of the automated AutoDock as a new docking tool for virtual screening.
  Proteins, 65, 549-554.  
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
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.  
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
15994308 H.Wang, Y.Liu, Y.Chen, H.Robinson, and H.Ke (2005).
Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7.
  J Biol Chem, 280, 30949-30955.
PDB code: 1zkl
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.  
16257373 M.D.Houslay, P.Schafer, and K.Y.Zhang (2005).
Keynote review: phosphodiesterase-4 as a therapeutic target.
  Drug Discov Today, 10, 1503-1519.  
16336277 S.Kunz, M.Oberholzer, and T.Seebeck (2005).
A FYVE-containing unusual cyclic nucleotide phosphodiesterase from Trypanosoma cruzi.
  FEBS J, 272, 6412-6422.  
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.