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PDBsum entry 1so2
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Catalytic domain of human phosphodiesterase 3b in complex with a dihydropyridazine inhibitor
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Structure:
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Cgmp-inhibited 3',5'-cyclic phosphodiesterase b. Chain: a, b, c, d. Fragment: catalytic domain, residues 654-1073. Synonym: cyclic gmp inhibited phosphodiesterase b, cgi-pde b, cgipde1, cgip1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: pde3b. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Biol. unit:
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Not given
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Resolution:
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2.40Å
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R-factor:
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0.239
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R-free:
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0.277
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Authors:
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G.Scapin,S.B.Patel,C.Chung,J.P.Varnerin,S.D.Edmondson,A.Mastracchio, E.R.Parmee,J.W.Becker,S.B.Singh,L.H.Van Der Ploeg,M.R.Tota
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Key ref:
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G.Scapin
et al.
(2004).
Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity.
Biochemistry,
43,
6091-6100.
PubMed id:
DOI:
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Date:
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12-Mar-04
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Release date:
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11-May-04
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PROCHECK
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Headers
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References
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Q13370
(PDE3B_HUMAN) -
cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B from Homo sapiens
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Seq:
Struc:
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1112 a.a.
363 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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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
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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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Biochemistry
43:6091-6100
(2004)
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PubMed id:
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Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity.
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G.Scapin,
S.B.Patel,
C.Chung,
J.P.Varnerin,
S.D.Edmondson,
A.Mastracchio,
E.R.Parmee,
S.B.Singh,
J.W.Becker,
L.H.Van der Ploeg,
M.R.Tota.
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ABSTRACT
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Phosphodiesterases (PDEs) are enzymes that modulate cyclic nucleotide signaling
and as such are clinical targets for a range of disorders including congestive
heart failure, erectile dysfunction, and inflammation. The PDE3 family comprises
two highly homologous subtypes expressed in different tissues, and inhibitors of
this family have been shown to increase lipolysis in adipocytes. A specific
PDE3B (the lipocyte-localized subtype) inhibitor would be a very useful tool to
evaluate the effects of PDE3 inhibition on lipolysis and metabolic rate and
might become a novel tool for treatment of obesity. We report here the
three-dimensional structures of the catalytic domain of human PDE3B in complex
with a generic PDE inhibitor and a novel PDE3 selective inhibitor. These
structures explain the dual cAMP/cGMP binding capabilities of PDE3, provide the
molecular basis for inhibitor specificity, and can supply a valid platform for
the design of improved compounds.
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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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R.E.Hubbard
(2011).
Structure-based drug discovery and protein targets in the CNS.
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Neuropharmacology,
60,
7.
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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.
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Bioorg Med Chem Lett,
21,
3307-3312.
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W.C.Lee,
H.C.Chen,
C.Y.Wang,
P.Y.Lin,
T.T.Ou,
C.C.Chen,
M.C.Wen,
J.Wang,
and
H.J.Lee
(2010).
Cilostazol ameliorates nephropathy in type 1 diabetic rats involving improvement in oxidative stress and regulation of TGF-Beta and NF-kappaB.
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Biosci Biotechnol Biochem,
74,
1355-1361.
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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.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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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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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,
Y.Liu,
J.Hou,
M.Zheng,
H.Robinson,
and
H.Ke
(2007).
Structural insight into substrate specificity of phosphodiesterase 10.
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Proc Natl Acad Sci U S A,
104,
5782-5787.
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PDB codes:
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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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M.Conti,
and
J.Beavo
(2007).
Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling.
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Annu Rev Biochem,
76,
481-511.
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W.M.Brown
(2007).
Treating COPD with PDE 4 inhibitors.
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Int J Chron Obstruct Pulmon Dis,
2,
517-533.
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W.Yuan,
and
A.López Bernal
(2007).
Cyclic AMP signalling pathways in the regulation of uterine relaxation.
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BMC Pregnancy Childbirth,
7,
S10.
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C.Lugnier
(2006).
Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.
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Pharmacol Ther,
109,
366-398.
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H.Wang,
Y.Liu,
Q.Huai,
J.Cai,
R.Zoraghi,
S.H.Francis,
J.D.Corbin,
H.Robinson,
Z.Xin,
G.Lin,
and
H.Ke
(2006).
Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development.
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J Biol Chem,
281,
21469-21479.
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PDB codes:
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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.
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J Med Chem,
49,
1867-1873.
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PDB codes:
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R.Zoraghi,
J.D.Corbin,
and
S.H.Francis
(2006).
Phosphodiesterase-5 Gln817 is critical for cGMP, vardenafil, or sildenafil affinity: its orientation impacts cGMP but not cAMP affinity.
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J Biol Chem,
281,
5553-5558.
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S.H.Hung,
W.Zhang,
R.A.Pixley,
B.A.Jameson,
Y.C.Huang,
R.F.Colman,
and
R.W.Colman
(2006).
New insights from the structure-function analysis of the catalytic region of human platelet phosphodiesterase 3A: a role for the unique 44-amino acid insert.
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J Biol Chem,
281,
29236-29244.
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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.
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Chem Biol,
12,
973-980.
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PDB codes:
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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.
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J Biol Chem,
280,
30949-30955.
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PDB code:
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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.
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Structure,
12,
2233-2247.
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PDB codes:
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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
