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PDBsum entry 1taz
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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 1b
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Structure:
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Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1b. Chain: a. Fragment: catalytic domain. Synonym: cam-pde 1b, 63 kda cam-pde. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: pde1b, pde1b1. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Biol. unit:
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Dimer (from
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Resolution:
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1.77Å
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R-factor:
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0.182
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R-free:
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0.193
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Authors:
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K.Y.J.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, G.Bollag
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Key ref:
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K.Y.Zhang
et al.
(2004).
A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases.
Mol Cell,
15,
279-286.
PubMed id:
DOI:
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Date:
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19-May-04
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Release date:
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03-Aug-04
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PROCHECK
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Headers
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References
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Q01064
(PDE1B_HUMAN) -
Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B from Homo sapiens
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Seq:
Struc:
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536 a.a.
322 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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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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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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Mol Cell
15:279-286
(2004)
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PubMed id:
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A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases.
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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,
G.Bollag.
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ABSTRACT
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Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the immune
response, inflammation, and memory, among many other functions. There are three
types of PDEs: cAMP-specific, cGMP-specific, and dual-specific. Here we describe
the mechanism of nucleotide selectivity on the basis of high-resolution
co-crystal structures of the cAMP-specific PDE4B and PDE4D with AMP, the
cGMP-specific PDE5A with GMP, and the apo-structure of the dual-specific PDE1B.
These structures show that an invariant glutamine functions as the key
specificity determinant by a "glutamine switch" mechanism for
recognizing the purine moiety in cAMP or cGMP. The surrounding residues anchor
the glutamine residue in different orientations for cAMP and for cGMP. The PDE1B
structure shows that in dual-specific PDEs a key histidine residue may enable
the invariant glutamine to toggle between cAMP and cGMP. The structural
understanding of nucleotide binding enables the design of new PDE inhibitors
that may treat diseases in which cyclic nucleotides play a critical role.
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Selected figure(s)
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Figure 1.
Figure 1. Crystal Structures of PDE1B, PDE4B, PDE4D, and
PDE5A in Complex with AMP or GMPThe overall structures of PDE1B,
PDE4B, PDE4D, and PDE5A are represented by ribbon diagrams
colored red, cyan, blue, and green, respectively. Zinc and
magnesium ions are represented by yellow and magenta spheres,
respectively. This color scheme is used throughout the figures
of this report. (A)–(D) have the same view looking down the
nucleotide binding pocket for ready comparison. The sixteen
helices are labeled in all four PDEs. In each case, positions of
all 17 invariant residues are highlighted in yellow. (E)–(G)
have the same zoom-in view of the active site. (A) PDE1B
apo-structure. (B) PDE4B in complex with AMP. Conventional
atomic color coding is used to represent AMP except carbon atoms
are colored green. (C) PDE4D in complex with AMP. (D) PDE5A
chimera in complex with GMP. Conventional atomic color coding is
used to represent GMP except carbon atoms are colored yellow.
(E) Superposition of PDE4B+AMP, PDE4D+AMP, and PDE5A+GMP show
conserved binding mode of nucleotides. The PDE nucleotide
binding site can be divided into four regions: nucleotide
recognition, hydrophobic clamp, metal binding, and hydrolysis.
(F) Overlay of PDE4D with AMP or Rolipram reveals conserved
binding interactions. (G) Overlay of PDE5A with GMP or
Sildenafil reveals conserved binding interactions. The
pyrazolopyrimidinone group of Sildenafil mimics the guanine in
GMP and they overlap in space. They both are sandwiched by the
hydrophobic clamp and also make the same bidentate H-bonds with
the conserved Q817.
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Figure 2.
Figure 2. The Conserved Glutamine Is the Primary
Selectivity Switch that Confers Nucleotide Specificity to
PDEsThe protein ribbons for PDE1B, PDE4D, and PDE5A are
represented by red, blue, and green, respectively. The
ball-and-stick representation of protein side chains and
nucleotides follows the same color scheme as in Figure 1. (A)
Q369 recognizing AMP in PDE4D. Q369 forms a bidentate H-bond
with the adenine moiety. Specifically, the Nε atom of Q369
donates an H-bond to the N1 atom of the adenine ring and the Oε
accepts a H-bond from N6 in the exocyclic amino group of
adenine. This particular orientation of Q369 is stabilized by
H-bonding of Oε to the phenolic hydroxyl Oη of Y329. In
addition, N321 forms a bidentate H-bond with the adenine base by
donating one H-bond from Nδ to N7 of the adenine base and
accepting one H-bond from the N6 of the exocyclic amino group to
its Oδ. (B) Q817 recognizing GMP in PDE5A. Q817 forms a
bidentate H-bond with GMP. The particular orientation of the
Q817 side chain is anchored by its H-bond interaction with Q775.
The orientation of Q775 side chain is in turn anchored by the
H-bond between Nε in Q775 and the carbonyl oxygen in A767 and
the H-bond between Oε of Q775 and the Nε of W853. (C) Q421
recognizing AMP in the model of AMP bound to PDE1B. (D) Q421
recognizing GMP in the model of GMP bound to PDE1B. In (C) and
(D), there are no supporting residues to anchor the orientation
of the key glutamine residue.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2004,
15,
279-286)
copyright 2004.
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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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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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P.V.Mazin,
M.S.Gelfand,
A.A.Mironov,
A.B.Rakhmaninova,
A.R.Rubinov,
R.B.Russell,
and
O.V.Kalinina
(2010).
An automated stochastic approach to the identification of the protein specificity determinants and functional subfamilies.
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Algorithms Mol Biol,
5,
29.
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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.
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EMBO J,
28,
3613-3622.
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PDB codes:
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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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P.Dadvar,
M.O'Flaherty,
A.Scholten,
K.Rumpel,
and
A.J.Heck
(2009).
A chemical proteomics based enrichment technique targeting the interactome of the PDE5 inhibitor PF-4540124.
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Mol Biosyst,
5,
472-482.
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C.C.Heikaus,
J.R.Stout,
M.R.Sekharan,
C.M.Eakin,
P.Rajagopal,
P.S.Brzovic,
J.A.Beavo,
and
R.E.Klevit
(2008).
Solution structure of the cGMP binding GAF domain from phosphodiesterase 5: insights into nucleotide specificity, dimerization, and cGMP-dependent conformational change.
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J Biol Chem,
283,
22749-22759.
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PDB code:
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D.M.Halpin
(2008).
ABCD of the phosphodiesterase family: interaction and differential activity in COPD.
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Int J Chron Obstruct Pulmon Dis,
3,
543-561.
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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.
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Biochem Pharmacol,
75,
1717-1728.
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PDB code:
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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.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.
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Mol Pharmacol,
73,
104-110.
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PDB code:
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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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T.Mostafa
(2008).
Oral phosphodiesterase-5 inhibitors and sperm functions.
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Int J Impot Res,
20,
530-536.
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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.
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J Biol Chem,
283,
29699-29705.
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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.
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J Comput Chem,
29,
1259-1267.
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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,
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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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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Y.H.Su,
and
V.D.Vacquier
(2006).
Cyclic GMP-specific phosphodiesterase-5 regulates motility of sea urchin spermatozoa.
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Mol Biol Cell,
17,
114-121.
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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.
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Biophys J,
91,
1858-1867.
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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.
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J Gen Physiol,
128,
413-422.
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D.A.Ryjenkov,
M.Tarutina,
O.V.Moskvin,
and
M.Gomelsky
(2005).
Cyclic diguanylate is a ubiquitous signaling molecule in bacteria: insights into biochemistry of the GGDEF protein domain.
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J Bacteriol,
187,
1792-1798.
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G.L.Card,
L.Blasdel,
B.P.England,
C.Zhang,
Y.Suzuki,
S.Gillette,
D.Fong,
P.N.Ibrahim,
D.R.Artis,
G.Bollag,
M.V.Milburn,
S.H.Kim,
J.Schlessinger,
and
K.Y.Zhang
(2005).
A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design.
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Nat Biotechnol,
23,
201-207.
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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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J.Aishima,
D.S.Russel,
L.J.Guibas,
P.D.Adams,
and
A.T.Brunger
(2005).
Automated crystallographic ligand building using the medial axis transform of an electron-density isosurface.
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Acta Crystallogr D Biol Crystallogr,
61,
1354-1363.
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K.Y.Zhang,
P.N.Ibrahim,
S.Gillette,
and
G.Bollag
(2005).
Phosphodiesterase-4 as a potential drug target.
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Expert Opin Ther Targets,
9,
1283-1305.
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L.I.Castro,
C.Hermsen,
J.E.Schultz,
and
J.U.Linder
(2005).
Adenylyl cyclase Rv0386 from Mycobacterium tuberculosis H37Rv uses a novel mode for substrate selection.
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FEBS J,
272,
3085-3092.
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M.D.Houslay,
P.Schafer,
and
K.Y.Zhang
(2005).
Keynote review: phosphodiesterase-4 as a therapeutic target.
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Drug Discov Today,
10,
1503-1519.
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C.Marshall,
and
W.Müller-Esterl
(2004).
Spotlight on cellular signaling.
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Mol Cell,
15,
849-852.
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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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M.Conti
(2004).
A view into the catalytic pocket of cyclic nucleotide phosphodiesterases.
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Nat Struct Mol Biol,
11,
809-810.
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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
