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PDBsum entry 2zb4
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Oxidoreductase
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PDB id
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2zb4
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References listed in PDB file
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Key reference
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Title
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Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase ptgr2.
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Authors
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Y.H.Wu,
T.P.Ko,
R.T.Guo,
S.M.Hu,
L.M.Chuang,
A.H.Wang.
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Ref.
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Structure, 2008,
16,
1714-1723.
[DOI no: ]
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PubMed id
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Abstract
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PTGR2 catalyzes an NADPH-dependent reduction of the conjugated
alpha,beta-unsaturated double bond of 15-keto-PGE(2), a key step in terminal
inactivation of prostaglandins and suppression of PPARgamma-mediated adipocyte
differentiation. Selective inhibition of PTGR2 may contribute to the improvement
of insulin sensitivity with fewer side effects. PTGR2 belongs to the
medium-chain dehydrogenase/reductase superfamily. The crystal structures
reported here reveal features of the NADPH binding-induced conformational change
in a LID motif and a polyproline type II helix which are critical for the
reaction. Mutation of Tyr64 and Tyr259 significantly reduces the rate of
catalysis but increases the affinity to substrate, confirming the structural
observations. Besides targeting cyclooxygenase, indomethacin also inhibits PTGR2
with a binding mode similar to that of 15-keto-PGE(2). The LID motif becomes
highly disordered upon the binding of indomethacin, indicating plasticity of the
active site. This study has implications for the rational design of inhibitors
of PTGR2.
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Figure 2.
Figure 2. Structure-Based Sequence Alignment of PTGR2 and
Homologs
(A) Stereo view of the crystal structure of the
hPTGR2-NADP^+-15-keto-PGE[2] complex. The nucleotide-binding
domain (H149–Y292) and catalytic domain (M1-G148; K293–L351)
are colored in purple and orange, respectively. The NADP^+
(yellow carbons), 15-keto-PGE[2] (green carbons), and sulfate
ions (dark yellow sulfurs) are shown as ball-and-stick models.
(B) Multiple sequence alignments of human PTGR2 (SwissProt
entry Q8N8N7), mouse PTGR2 (Q3TG36), guinea pig 13-PGR/LTB[4]DH
(Q9EQZ5), and human 13-PGR/LTB[4]DH (A8K0N2). The LID motifs and
PPII helices of PTGR2 are indicated by double-headed arrows. The
conserved nucleotide-binding motif is underlined. Tyr64 and
Tyr259 are marked with red boxes.
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Figure 6.
Figure 6. Putative Catalytic Residues
Alignment of the
active sites of hPTGR2 (cyan), mPTGR2 (magenta), 13-PGR/LTB[4]DH
(yellow), and Etr1p (gray). Hydrogen bonds in PTGR2 and Etr1p
are in red and blue, respectively. Tyr262(B) is from the
countersubunit B of 13-PGR/LTB[4]DH.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2008,
16,
1714-1723)
copyright 2008.
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