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* Residue conservation analysis
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Enzyme class:
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Chains A, B:
E.C.3.1.4.17
- 3',5'-cyclic-nucleotide phosphodiesterase.
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Reaction:
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a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-phosphate + H+
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nucleoside 3',5'-cyclic phosphate
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+
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H2O
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=
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nucleoside 5'-phosphate
Bound ligand (Het Group name = )
matches with 52.00% similarity
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Proc Natl Acad Sci U S A
104:5782-5787
(2007)
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PubMed id:
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Structural insight into substrate specificity of phosphodiesterase 10.
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H.Wang,
Y.Liu,
J.Hou,
M.Zheng,
H.Robinson,
H.Ke.
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ABSTRACT
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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.
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Selected figure(s)
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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).
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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.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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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.
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PLoS One,
6,
e18092.
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PDB codes:
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Z.Zhang,
and
N.O.Artemyev
(2010).
Determinants for phosphodiesterase 6 inhibition by its gamma-subunit.
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Biochemistry,
49,
3862-3867.
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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.
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J Pharmacol Exp Ther,
331,
133-141.
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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.
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Proc Natl Acad Sci U S A,
106,
18225-18230.
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PDB codes:
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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.
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Acta Crystallogr D Biol Crystallogr,
65,
872-874.
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PDB code:
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Z.Yan,
H.Wang,
J.Cai,
and
H.Ke
(2009).
Refolding and kinetic characterization of the phosphodiesterase-8A catalytic domain.
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Protein Expr Purif,
64,
82-88.
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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.
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Cell Signal,
20,
10-20.
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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.
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J Neurochem,
105,
546-556.
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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.
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Biochemistry,
47,
12760-12768.
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PDB codes:
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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.
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Proc Natl Acad Sci U S A,
105,
13309-13314.
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PDB codes:
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H.Wang,
H.Robinson,
and
H.Ke
(2007).
The molecular basis for different recognition of substrates by phosphodiesterase families 4 and 10.
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J Mol Biol,
371,
302-307.
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PDB code:
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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.
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Mol Microbiol,
66,
1029-1038.
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PDB code:
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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.
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Links
