PDBsum entry 2our

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
Protein chain
324 a.a. *
_MG ×2
Waters ×433
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of pde10a2 mutant d674a in complex with camp
Structure: Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: catalytic domain. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Strain: pde10a2. Gene: pde10a. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
1.45Å     R-factor:   0.218     R-free:   0.236
Authors: H.C.Wang,Y.D.Liu,J.Hou,M.Y.Zheng,H.Robinson
Key ref:
H.Wang et al. (2007). Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A, 104, 5782-5787. PubMed id: 17389385 DOI: 10.1073/pnas.0700279104
12-Feb-07     Release date:   20-Mar-07    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q9Y233  (PDE10_HUMAN) -  cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
779 a.a.
324 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: E.C.  - 3',5'-cyclic-nucleotide phosphodiesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Nucleoside 3',5'-cyclic phosphate + H2O = nucleoside 5'-phosphate
Nucleoside 3',5'-cyclic phosphate
Bound ligand (Het Group name = CMP)
matches with 52.00% similarity
+ H(2)O
= nucleoside 5'-phosphate
   Enzyme class 2: 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 = CMP)
matches with 95.00% similarity
+ H(2)O
= guanosine 5'-phosphate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
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  


DOI no: 10.1073/pnas.0700279104 Proc Natl Acad Sci U S A 104:5782-5787 (2007)
PubMed id: 17389385  
Structural insight into substrate specificity of phosphodiesterase 10.
H.Wang, Y.Liu, J.Hou, M.Zheng, H.Robinson, H.Ke.
Phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. It remains unknown how individual PDE families selectively recognize cAMP and cGMP. This work reports structural studies on substrate specificity. The crystal structures of the catalytic domains of the D674A and D564N mutants of PDE10A2 in complex with cAMP and cGMP reveal that two substrates bind to the active site with the same syn configuration but different orientations and interactions. The products AMP and GMP bind PDE10A2 with the anti configuration and interact with both divalent metals, in contrast to no direct contact of the substrates. The structures suggest that the syn configurations of cAMP and cGMP are the genuine substrates for PDE10 and the specificity is achieved through the different interactions and conformations of the substrates. The PDE10A2 structures also show that the conformation of the invariant glutamine is locked by two hydrogen bonds and is unlikely to switch for substrate recognition. Sequence alignment shows a potential pocket, in which variation of amino acids across PDE families defines the size and shape of the pocket and thus determines the substrate specificity.
  Selected figure(s)  
Figure 3.
Fig. 3. Binding of products. (A) Interaction of AMP (gold) with PDE10A2 residues (green). (B) Interaction of GMP with PDE10A2 residues. (C) Superposition of PDE10A2-AMP over PDE4D2-AMP (salmon sticks) (27). (D) Superposition of AMP (pink) over cAMP (gold).
Figure 4.
Fig. 4. A potential S-pocket. (A) The PDE10A2 residues (green bonds) are superimposed over the PDE4D2 residues (thinner salmon sticks). (B) Surface presentation of the S-pocket in PDE10.
  Figures were selected by an automated process.  

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
20397626 Z.Zhang, and N.O.Artemyev (2010).
Determinants for phosphodiesterase 6 inhibition by its gamma-subunit.
  Biochemistry, 49, 3862-3867.  
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
19622871 O.A.Andersen, D.L.Schönfeld, I.Toogood-Johnson, B.Felicetti, C.Albrecht, T.Fryatt, M.Whittaker, D.Hallett, and J.Barker (2009).
Cross-linking of protein crystals as an aid in the generation of binary protein-ligand crystal complexes, exemplified by the human PDE10a-papaverine structure.
  Acta Crystallogr D Biol Crystallogr, 65, 872-874.
PDB code: 2wey
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.  
17716863 G.G.Holz, O.G.Chepurny, and F.Schwede (2008).
Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors.
  Cell Signal, 20, 10-20.  
18088367 H.Sano, Y.Nagai, T.Miyakawa, R.Shigemoto, and M.Yokoi (2008).
Increased social interaction in mice deficient of the striatal medium spiny neuron-specific phosphodiesterase 10A2.
  J Neurochem, 105, 546-556.  
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
17582435 H.Wang, H.Robinson, and H.Ke (2007).
The molecular basis for different recognition of substrates by phosphodiesterase families 4 and 10.
  J Mol Biol, 371, 302-307.
PDB code: 2pw3
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.