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PDBsum entry 3cwl
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Protease inhibitor
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PDB id
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3cwl
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References listed in PDB file
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Key reference
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Title
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Preventing serpin aggregation: the molecular mechanism of citrate action upon antitrypsin unfolding.
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Authors
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M.C.Pearce,
C.J.Morton,
S.C.Feil,
G.Hansen,
J.J.Adams,
M.W.Parker,
S.P.Bottomley.
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Ref.
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Protein Sci, 2008,
17,
2127-2133.
[DOI no: ]
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PubMed id
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Abstract
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The aggregation of antitrypsin into polymers is one of the causes of neonatal
hepatitis, cirrhosis, and emphysema. A similar reaction resulting in disease can
occur in other human serpins, and collectively they are known as the
serpinopathies. One possible therapeutic strategy involves inhibiting the
conformational changes involved in antitrypsin aggregation. The citrate ion has
previously been shown to prevent antitrypsin aggregation and maintain the
protein in an active conformation; its mechanism of action, however, is unknown.
Here we demonstrate that the citrate ion prevents the initial misfolding of the
native state to a polymerogenic intermediate in a concentration-dependent
manner. Furthermore, we have solved the crystal structure of citrate bound to
antitrypsin and show that a single citrate molecule binds in a pocket between
the A and B beta-sheets, a region known to be important in maintaining
antitrypsin stability.
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Figure 3.
Diagrammatic representation of the three-dimensional
structure of the AAT --citrate complex. The protein is shown in
ribbon style, with sheet A in blue, sheet B in red, sheet C in
yellow, the reactive center loop in green, and the citrate ion
is shown as cyan-colored spheres.
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Figure 4.
Analysis of the citrate-binding pocket. Stereoscopic figure
of residues contributing to the citrate-binding pocket in (A)
crystal form A, (B) crystal form B, and (C) the citrate complex.
In all three, the protein is shown as sticks colored by atom
type (carbon: green, oxygen: red, nitrogen: blue, sulfur:
yellow), with water molecules shown as red spheres. In crystal
form B, the chloride ion is shown as an orange sphere (B) while
in the citrate complex (B) the citrate is shown as sticks
colored by atom type, except that the carbon atoms are in cyan.
Comparison of the three sites shows that minimal rearrangement
of the site has occurred to adapt to citrate binding.
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(2008,
17,
2127-2133)
copyright 2008.
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