PDBsum entry 1rkp

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Hydrolase PDB id
Jmol PyMol
Protein chain
311 a.a. *
Waters ×133
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of pde5a1-ibmx
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. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pde5a, pde5, pde5a1. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.05Å     R-factor:   0.220     R-free:   0.243
Authors: Q.Huai,Y.Liu,S.H.Francis,J.D.Corbin,H.Ke
Key ref:
Q.Huai et al. (2004). Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity. J Biol Chem, 279, 13095-13101. PubMed id: 14668322 DOI: 10.1074/jbc.M311556200
22-Nov-03     Release date:   30-Mar-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O76074  (PDE5A_HUMAN) -  cGMP-specific 3',5'-cyclic phosphodiesterase
875 a.a.
311 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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
Bound ligand (Het Group name = IBM)
matches with 50.00% similarity
+ 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: 10.1074/jbc.M311556200 J Biol Chem 279:13095-13101 (2004)
PubMed id: 14668322  
Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity.
Q.Huai, Y.Liu, S.H.Francis, J.D.Corbin, H.Ke.
Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes controlling cellular concentrations of the second messengers cAMP and cGMP. Crystal structures of the catalytic domains of cGMP-specific PDE5A1 and cAMP-specific PDE4D2 in complex with the nonselective inhibitor 3-isobutyl-1-methylxanthine have been determined at medium resolution. The catalytic domain of PDE5A1 has the same topological folding as that of PDE4D2, but three regions show different tertiary structures, including residues 79-113, 208-224 (H-loop), and 341-364 (M-loop) in PDE4D2 or 535-566, 661-676, and 787-812 in PDE5A1, respectively. Because H- and M-loops are involved in binding of the selective inhibitors, the different conformations of the loops, thus the distinct shapes of the active sites, will be a determinant of inhibitor selectivity in PDEs. IBMX binds to a subpocket that comprises key residues Ile-336, Phe-340, Gln-369, and Phe-372 of PDE4D2 or Val-782, Phe-786, Gln-817, and Phe-820 of PDE5A1. This subpocket may be a common site for binding nonselective inhibitors of PDEs.
  Selected figure(s)  
Figure 1.
FIG. 1. Structures of the PDE-IBMX complexes. A, ribbon diagram of PDE4D2-IBMX. The -helices are colored as cyan, and blue color represents 3[10] helices. The first metal ion is interpreted as zinc, as discussed previously (31, 33), whereas the second metal ion (Me2) is ambiguous. B, ribbon diagram of PDE5A1-IBMX. The second metal ion was assigned as magnesium because 0.2 M MgSO[4] was used in the crystallization buffer. C, the structural superposition between PDE4D2 and PDE5A1. The cyan ribbons represent the conserved core structures between PDE4D2 and PDE5A1. The variable regions are drawn in gold for PDE4D2 and green for PDE5A1. D, the correspondence of amino acid sequence to the secondary structures.
Figure 2.
FIG. 2. IBMX binding. Stereoview of the electron density for IBMX bound to PDE4D2 (A) and PDE5A1 (B). The 2F[o] - F[c] maps were calculated from the structures omitted IBMX and contoured at 1.5 for PDE4D2 and 2.0 for PDE5A1. C, chemical structure of IBMX. D, IBMX binding to the active site of PDE4D2. The xanthine group stacks against Phe-372 and forms hydrogen bond with Gln-369 (dotted lines). E, IBMX binding to the active site of PDE5A1.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 13095-13101) copyright 2004.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20862763 R.Raijmakers, P.Dadvar, S.Pelletier, J.Gouw, K.Rumpel, and A.J.Heck (2010).
Target profiling of a small library of phosphodiesterase 5 (PDE5) inhibitors using chemical proteomics.
  ChemMedChem, 5, 1927-1936.  
20363937 Y.Zhang, E.L.Pohlmann, J.Serate, M.C.Conrad, and G.P.Roberts (2010).
Mutagenesis and functional characterization of the four domains of GlnD, a bifunctional nitrogen sensor protein.
  J Bacteriol, 192, 2711-2721.  
20397626 Z.Zhang, and N.O.Artemyev (2010).
Determinants for phosphodiesterase 6 inhibition by its gamma-subunit.
  Biochemistry, 49, 3862-3867.  
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
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
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
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
19049349 S.Zheng, G.Kaur, H.Wang, M.Li, M.Macnaughtan, X.Yang, S.Reid, J.Prestegard, B.Wang, and H.Ke (2008).
Design, synthesis, and structure-activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors.
  J Med Chem, 51, 7673-7688.  
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.  
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
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.  
17242516 N.Kondo, N.Nakagawa, A.Ebihara, L.Chen, Z.J.Liu, B.C.Wang, S.Yokoyama, S.Kuramitsu, and R.Masui (2007).
Structure of dNTP-inducible dNTP triphosphohydrolase: insight into broad specificity for dNTPs and triphosphohydrolase-type hydrolysis.
  Acta Crystallogr D Biol Crystallogr, 63, 230-239.
PDB code: 2dqb
  17565173 V.Oganesyan, P.D.Adams, J.Jancarik, R.Kim, and S.H.Kim (2007).
Structure of O67745_AQUAE, a hypothetical protein from Aquifex aeolicus.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 369-374.
PDB code: 2hek
16102838 C.Lugnier (2006).
Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.
  Pharmacol Ther, 109, 366-398.  
18044094 D.Wang, and X.Cui (2006).
Evaluation of PDE4 inhibition for COPD.
  Int J Chron Obstruct Pulmon Dis, 1, 373-379.  
16883306 H.A.Ghofrani, I.H.Osterloh, and F.Grimminger (2006).
Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.
  Nat Rev Drug Discov, 5, 689-702.  
16394525 H.Suzuki, H.Sawanishi, M.Nomura, T.Shimada, and K.Miyamoto (2006).
Effects of 1-benzylxanthines on cyclic AMP phosphodiesterase 4 isoenzyme.
  Biol Pharm Bull, 29, 131-134.  
16420250 K.S.Kim, J.A.Kim, S.Y.Eom, S.H.Lee, K.R.Min, and Y.Kim (2006).
Inhibitory effect of piperlonguminine on melanin production in melanoma B16 cell line by downregulation of tyrosinase expression.
  Pigment Cell Res, 19, 90-98.  
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.  
  16966475 Z.Zhou, X.Wang, H.Y.Liu, X.Zou, M.Li, and T.C.Hwang (2006).
The two ATP binding sites of cystic fibrosis transmembrane conductance regulator (CFTR) play distinct roles in gating kinetics and energetics.
  J Gen Physiol, 128, 413-422.  
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.  
16183021 F.V.Rao, O.A.Andersen, K.A.Vora, J.A.Demartino, and D.M.van Aalten (2005).
Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes.
  Chem Biol, 12, 973-980.
PDB codes: 2a3a 2a3b 2a3c 2a3e
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.  
16123402 X.Zhang, Q.Feng, and R.H.Cote (2005).
Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors.
  Invest Ophthalmol Vis Sci, 46, 3060-3066.  
16223764 Z.Zhou, X.Wang, M.Li, Y.Sohma, X.Zou, and T.C.Hwang (2005).
High affinity ATP/ADP analogues as new tools for studying CFTR gating.
  J Physiol, 569, 447-457.  
15576036 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, and K.Y.Zhang (2004).
Structural basis for the activity of drugs that inhibit phosphodiesterases.
  Structure, 12, 2233-2247.
PDB codes: 1xlx 1xlz 1xm4 1xm6 1xmu 1xmy 1xn0 1xom 1xon 1xoq 1xor 1xos 1xot 1xoz 1xp0
15260978 K.Y.Zhang, G.L.Card, Y.Suzuki, D.R.Artis, D.Fong, S.Gillette, D.Hsieh, J.Neiman, B.L.West, C.Zhang, M.V.Milburn, S.H.Kim, J.Schlessinger, and G.Bollag (2004).
A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases.
  Mol Cell, 15, 279-286.
PDB codes: 1t9r 1t9s 1taz 1tb5 1tb7 1tbb 1tbf
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.