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PDBsum entry 1v04
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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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Structure and evolution of the serum paraoxonase family of detoxifying and anti-Atherosclerotic enzymes.
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Authors
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M.Harel,
A.Aharoni,
L.Gaidukov,
B.Brumshtein,
O.Khersonsky,
R.Meged,
H.Dvir,
R.B.Ravelli,
A.Mccarthy,
L.Toker,
I.Silman,
J.L.Sussman,
D.S.Tawfik.
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Ref.
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Nat Struct Mol Biol, 2004,
11,
412-419.
[DOI no: ]
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PubMed id
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Abstract
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Members of the serum paraoxonase (PON) family have been identified in mammals
and other vertebrates, and in invertebrates. PONs exhibit a wide range of
physiologically important hydrolytic activities, including drug metabolism and
detoxification of nerve agents. PON1 and PON3 reside on high-density lipoprotein
(HDL, 'good cholesterol') and are involved in the prevention of atherosclerosis.
We describe the first crystal structure of a PON family member, a variant of
PON1 obtained by directed evolution, at a resolution of 2.2 A. PON1 is a
six-bladed beta-propeller with a unique active site lid that is also involved in
HDL binding. The three-dimensional structure and directed evolution studies
permit a detailed description of PON1's active site and catalytic mechanism,
which are reminiscent of secreted phospholipase A2, and of the routes by which
PON family members diverged toward different substrate and reaction
selectivities.
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Figure 2.
Figure 2. PON1's active site viewed from above the propeller.
(a) Central tunnel of the propeller with the two calcium atoms,
and the side chains of the residues found to be mutated in the
newly evolved PON1 variants for esterase and lactonase (orange)
or for phosphotriesterase activity (yellow), including the R192Q
human polymorphism (in the rePON1-G2E6 variant, this position is
a lysine). The putative catalytic His-His dyad is red (see text
and Fig. 4). (b) A surface view of the active site. Lys70, Tyr71
and Phe347 are shown as sticks to permit a better view of the
active site. At the deepest point of the cavity lies the upper
calcium atom (Ca1, green) to which a phosphate ion is bound.
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Figure 6.
Figure 6. Proposed model for anchoring of PON1 to the surface of
HDL. (a) Tertiary structure cartoon of rePON1 showing its
exposed hydrophobic surfaces. N-terminal residues 7 -18, missing
in the crystal structure and predicted to be helical, were
modeled as part of H1. Denoted are all the hydrophobic residues
(leucine, phenylalanine, proline, isoleucine, tyrosine,
tryptophan and valine) appearing with accessible surface area
 20
Å2. (b) Hydrophobic residues proposed to be involved in HDL
anchoring (side chains yellow). The line defined by the side
chains of Tyr185, Phe 186, Tyr190, Trp194, Trp202 (helix H2 and
the adjacent loops) and Lys21 (helix H1) models the putative
interface between HDL's hydrophobic interior and the exterior
aqueous phase. The hydrophobic side chains of leucine and
phenylalanine residues of H1 are primarily within the apolar
region31. The active site and the selectivity-determining
residues (Table 2) are blue, and the proposed glycosylation
sites (Asn253 and Asn324) are red.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2004,
11,
412-419)
copyright 2004.
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