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PDBsum entry 1d3v
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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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Arginase-Boronic acid complex highlights a physiological role in erectile function.
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Authors
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J.D.Cox,
N.N.Kim,
A.M.Traish,
D.W.Christianson.
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Ref.
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Nat Struct Biol, 1999,
6,
1043-1047.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of the complex between the binuclear manganese
metalloenzyme arginase and the boronic acid analog of L-arginine,
2(S)-amino-6-boronohexanoic acid (ABH), has been determined at 1.7 A resolution
from a crystal perfectly twinned by hemihedry. ABH binds as the tetrahedral
boronate anion, with one hydroxyl oxygen symmetrically bridging the binuclear
manganese cluster and a second hydroxyl oxygen coordinating to Mn2+A. This
binding mode mimics the transition state of a metal-activated hydroxide
mechanism. This transition state structure differs from that occurring in NO
biosynthesis, thereby explaining why ABH does not inhibit NO synthase. We also
show that arginase activity is present in the penis. Accordingly, the tight
binding and specificity of ABH allows us to probe the physiological role of
arginase in modulating the NO-dependent smooth muscle relaxation required for
erection. Strikingly, ABH causes significant enhancement of nonadrenergic,
noncholinergic nerve-mediated relaxation of penile corpus cavernosum smooth
muscle, suggesting that arginase inhibition sustains L-arginine concentrations
for NO synthase activity. Therefore, human penile arginase is a potential target
for therapeutic intervention in the treatment of erectile dysfunction.
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Figure 1.
Figure 1. L-Arginine catabolism. a, Structure-based mechanism
of arginase^16, in which metal-activated hydroxide ion attacks
the substrate guanidinium group to form a tetrahedral
intermediate (for clarity, only the side chain atoms of
substrate L-arginine are shown). Proton transfer mediated by Asp
128 facilitates collapse of this intermediate to form products
L-ornithine and urea. Following product dissociation, a
nucleophilic metal-bridging hydroxide ion is regenerated from a
metal-bridging water by proton transfer to bulk solvent. His 141
may function as a proton shuttle as indicated. b, Reciprocal
coordination of arginase and nitric oxide pathways; note that N^
 -hydroxy-L-arginine
is an intermediate in the NO synthase reaction. c, The arginase
inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) is an isostere
of L-arginine.
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Figure 2.
Figure 2. Arginase−ABH complex. a, Omit electron density
map of ABH in the arginase active site averaged over the two
monomers in the asymmetric unit and averaged over the two twin
domains A and B as described in the text. The map is contoured
at 7.7  and
selected active site residues are indicated. Atoms are
color-coded as follows: C = yellow, O = red, N = blue, B = pale
green; water molecules appear as red spheres. This figure was
generated with BOBSCRIPT and Raster3D^34, ^35. b, Summary of
arginase−ABH interactions; manganese coordination interactions
are designated by green dashed lines, and hydrogen bonds are
indicated by black dashed lines. c, Stabilization of the
tetrahedral intermediate (and flanking transition states) in the
arginase mechanism based on the binding mode of ABH.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(1999,
6,
1043-1047)
copyright 1999.
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