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PDBsum entry 1t9s
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases.
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Authors
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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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Ref.
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Mol Cell, 2004,
15,
279-286.
[DOI no: ]
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PubMed id
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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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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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