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PDBsum entry 2hd1

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
2hd1
Jmol
Contents
Protein chain
326 a.a. *
Ligands
IBM ×2
Metals
_ZN ×2
_MG ×2
Waters ×195
* Residue conservation analysis
PDB id:
2hd1
Name: Hydrolase
Title: Crystal structure of pde9 in complex with ibmx
Structure: Phosphodiesterase 9a. Chain: a, b. Fragment: catalytic domain (residues 181-506). Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pde. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Dimer (from PQS)
Resolution:
2.23Å     R-factor:   0.215     R-free:   0.231
Authors: Q.Huai,H.Wang,W.Zhang,R.W.Colman,H.Robinson,H.Ke
Key ref:
Q.Huai et al. (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. PubMed id: 15210993 DOI: 10.1073/pnas.0401120101
Date:
19-Jun-06     Release date:   27-Jun-06    
Supersedes: 1tbm
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O76083  (PDE9A_HUMAN) -  High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Seq:
Struc:
 
Seq:
Struc:
593 a.a.
326 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.1.4.35  - 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: 10.1073/pnas.0401120101 Proc Natl Acad Sci U S A 101:9624-9629 (2004)
PubMed id: 15210993  
 
 
Crystal structure of phosphodiesterase 9 shows orientation variation of inhibitor 3-isobutyl-1-methylxanthine binding.
Q.Huai, H.Wang, W.Zhang, R.W.Colman, H.Robinson, H.Ke.
 
  ABSTRACT  
 
Cyclic nucleotide phosphodiesterases (PDEs) are enzymes controlling cellular concentrations of the second messengers cAMP and cGMP. The crystal structure of the catalytic domain of PDE9A2, a member of a PDE family specifically hydrolyzing cGMP, has been determined at 2.23-A resolution. The PDE9A2 catalytic domain closely resembles the cAMP-specific PDE4D2 but is significantly different from the cGMP-specific PDE5A1, implying that each individual PDE family has its own characteristic substrate recognition mechanism. The different conformations of the H and M loops between PDE9A2 and PDE5A1 imply their less critical roles in nucleotide recognition. The nonselective inhibitor 3-isobutyl-1-methylxanthine (IBMX) binds to a similar subpocket in the active sites of PDE4, PDE5, and PDE9 and has a common pattern of the binding. However, significantly different orientations and interactions of IBMXs are observed among the three PDE families and also between two monomers of the PDE9A2 dimer. The kinetic properties of the PDE9A2 catalytic domain similar to those of full-length PDE9A imply that the N-terminal regulatory domain does not significantly alter the catalytic activity and the IBMX inhibition.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Ribbon presentation of dimers of PDE9A2 (A) and PDE4D2 (B) are shown, and the interface of the PDE9A2 dimer is shown in C.
Figure 3.
Fig. 3. IBMX binding. (A) Stereoview of the electron density for IBMX bound to PDE9A2. The (2F[o] - F[c]) map was calculated from the structure omitting IBMX and contoured at 2.0 . (B) IBMX binding to the active site of PDE9A2. The xanthine group stacks against Phe-456 and forms a hydrogen bond with Gln-453. The green balls-sticks represent IBMX in molecule A. The golden balls-sticks represent IBMX from molecule B, which is superimposed over molecule A. The dotted line represents a hydrogen bond. The PDE9A2 residues that interact with IBMX in both monomers are shown in blue sticks, whereas the unique residues interacting with IBMX in one monomer are drawn in green sticks (monomer A) and golden sticks (monomer B).
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21483814 J.Hou, J.Xu, M.Liu, R.Zhao, H.B.Luo, and H.Ke (2011).
Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic acid, and role of the invariant glutamine.
  PLoS One, 6, e18092.
PDB codes: 3qi3 3qi4
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
20397626 Z.Zhang, and N.O.Artemyev (2010).
Determinants for phosphodiesterase 6 inhibition by its gamma-subunit.
  Biochemistry, 49, 3862-3867.  
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
19429786 R.P.Norris, W.J.Ratzan, M.Freudzon, L.M.Mehlmann, J.Krall, M.A.Movsesian, H.Wang, H.Ke, V.O.Nikolaev, and L.A.Jaffe (2009).
Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte.
  Development, 136, 1869-1878.  
18984055 Z.Yan, H.Wang, J.Cai, and H.Ke (2009).
Refolding and kinetic characterization of the phosphodiesterase-8A catalytic domain.
  Protein Expr Purif, 64, 82-88.  
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
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.  
17561940 R.Hepp, L.Tricoire, E.Hu, N.Gervasi, D.Paupardin-Tritsch, B.Lambolez, and P.Vincent (2007).
Phosphodiesterase type 2 and the homeostasis of cyclic GMP in living thalamic neurons.
  J Neurochem, 102, 1875-1886.  
17090334 C.Rentero, and P.Puigdomènech (2006).
Specific use of start codons and cellular localization of splice variants of human phosphodiesterase 9A gene.
  BMC Mol Biol, 7, 39.  
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
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.  
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
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.