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PDBsum entry 3d5e
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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 structure of human plasma platelet-Activating factor acetylhydrolase: structural implication to lipoprotein binding and catalysis.
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Authors
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U.Samanta,
B.J.Bahnson.
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Ref.
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J Biol Chem, 2008,
283,
31617-31624.
[DOI no: ]
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PubMed id
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Abstract
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Human plasma platelet-activating factor (PAF) acetylhydrolase functions by
reducing PAF levels as a general anti-inflammatory scavenger and is linked to
anaphylactic shock, asthma, and allergic reactions. The enzyme has also been
implicated in hydrolytic activities of other pro-inflammatory agents, such as
sn-2 oxidatively fragmented phospholipids. This plasma enzyme is tightly bound
to low and high density lipoprotein particles and is also referred to as
lipoprotein-associated phospholipase A(2). The crystal structure of this enzyme
has been solved from x-ray diffraction data collected to a resolution of 1.5A.
It has a classic lipase alpha/beta-hydrolase fold, and it contains a catalytic
triad of Ser(273), His(351), and Asp(296). Two clusters of hydrophobic residues
define the probable interface-binding region, and a prediction is given of how
the enzyme is bound to lipoproteins. Additionally, an acidic patch of 10
carboxylate residues and a neighboring basic patch of three residues are
suggested to play a role in high density lipoprotein/low density lipoprotein
partitioning. A crystal structure is also presented of PAF acetylhydrolase
reacted with the organophosphate compound paraoxon via its active site Ser(273).
The resulting diethyl phosphoryl complex was used to model the tetrahedral
intermediate of the substrate PAF to the active site. The model of interface
binding begins to explain the known specificity of lipoprotein-bound substrates
and how the active site can be both close to the hydrophobic-hydrophilic
interface and at the same time be accessible to the aqueous phase.
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Figure 3.
Polymorphic sites of PAF-AH shown in gray ball and stick
relative to the active site Ser^273 and in a view looking
directly at the interfacial binding surface of the enzyme. Three
of the polymorphic sites (I198T, A379V, and R92H) are
solvent-accessible. Two loss of function polymorphisms (V279F
and Q281R) that lead to a loss of function in 4% of Japanese
individuals are core residues. This figure was rendered using
the program PyMOL (51).
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Figure 4.
A, model of the tetrahedral intermediate of C (cyan)
bound to PAF-AH with catalytic triad residues (Ser^273, His^351,
and Asp^296) in green and interfacial-binding residues (Thr^113,
His^114, Trp^115, Leu^116, Met^117, Ile^120, Leu^123, Leu^124,
Ile^364, Ile^365, Met^368, and Leu^369) in yellow. The
coordinates of the tetrahedral intermediate were modeled based
on the crystal structure of the DEP moiety complexed to PAF-AH
(tetrahedral mimic). The C[18]-alkyl chain was oriented to
penetrate into the hydrophobic portion of the LDL particle. The
predicted plane of the hydrophilic-hydrophobic interface, which
was predicted by the OPM method (47, 48), is displayed with
small gray spheres. B, the view from A was rotated by 90° on
the y axis to show a side view of the interface and
substrate-bound model. A prominent cluster of 10 carboxylate
residues (Asp^374, Asp^376, Asp^382, Asp^401, Asp^403, Asp^406,
Glu^410, Asp^412, Asp^413, and Glu^414) are shown in red, and
three basic residues (Lys^55, Arg^58, and Lys^363) are shown in
blue ball and stick. C, electrostatic surface view of A. D,
electrostatic surface view of B. The figure was prepared using
the program PyMOL (51).
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The above figures are
reprinted
from an Open Access publication published by the ASBMB:
J Biol Chem
(2008,
283,
31617-31624)
copyright 2008.
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