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PDBsum entry 2arm
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References listed in PDB file
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Key reference
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Title
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Crystal structures of the complexes of a group iia phospholipase a2 with two natural anti-Inflammatory agents, Anisic acid, And atropine reveal a similar mode of binding.
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Authors
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N.Singh,
T.Jabeen,
A.Pal,
S.Sharma,
M.Perbandt,
C.Betzel,
T.P.Singh.
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Ref.
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Proteins, 2006,
64,
89-100.
[DOI no: ]
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PubMed id
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Abstract
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Secretory low molecular weight phospholipase A(2)s (PLA(2)s) are believed to be
involved in the release of arachidonic acid, a precursor for the biosynthesis of
pro-inflammatory eicosanoids. Therefore, the specific inhibitors of these
enzymes may act as potent anti-inflammatory agents. Similarly, the compounds
with known anti-inflammatory properties should act as specific inhibitors. Two
plant compounds, (a) anisic acid (4-methoxy benzoic acid) and (b) atropine
(8-methyl-8-azabicyclo oct-3-hydroxy-2-phenylpropanoate), have been used in
various inflammatory disorders. Both compounds (a) and (b) have been found to
inhibit PLA(2) activity having binding constants of 4.5 x 10(-5) M and 2.1 x
10(-8) M, respectively. A group IIA PLA(2) was isolated and purified from the
venom of Daboia russelli pulchella (DRP) and its complexes were made with anisic
acid and atropine. The crystal structures of the two complexes (i) and (ii) of
PLA(2) with compounds (a) and (b) have been determined at 1.3 and 1.2 A
resolutions, respectively. The high-quality observed electron densities for the
two compounds allowed the accurate determinations of their atomic positions. The
structures revealed that these compounds bound to the enzyme at the substrate -
binding cleft and their positions were stabilized by networks of hydrogen bonds
and hydrophobic interactions. The most characteristic interactions involving Asp
49 and His 48 were clearly observed in both complexes, although the residues
that formed hydrophobic interactions with these compounds were not identical
because their positions did not exactly superimpose in the large
substrate-binding hydrophobic channel. Owing to a relatively small size, the
structure of anisic acid did not alter upon binding to PLA(2), while that of
atropine changed significantly when compared with its native crystal structure.
The conformation of the protein also did not show notable changes upon the
bindings of these ligands. The mode of binding of anisic acid to the present
group II PLA(2) is almost identical to its binding with bovine pancreatic PLA(2)
of group I. On the other hand, the binding of atropine to PLA(2) is similar to
that of another plant alkaloid aristolochic acid.
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Figure 5.
Figure 5.
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Figure 6.
Figure 6. The superimposition of atropine (yellow) from the
present structure on its structure in the uncomplexed states
(blue).
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2006,
64,
89-100)
copyright 2006.
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