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PDBsum entry 1ezx
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Hydrolase/hydrolase inhibitor
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PDB id
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1ezx
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Contents |
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335 a.a.
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36 a.a.
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140 a.a.
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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 of a serpin-Protease complex shows inhibition by deformation.
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Authors
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J.A.Huntington,
R.J.Read,
R.W.Carrell.
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Ref.
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Nature, 2000,
407,
923-926.
[DOI no: ]
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PubMed id
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Abstract
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The serpins have evolved to be the predominant family of serine-protease
inhibitors in man. Their unique mechanism of inhibition involves a profound
change in conformation, although the nature and significance of this change has
been controversial. Here we report the crystallographic structure of a typical
serpin-protease complex and show the mechanism of inhibition. The conformational
change is initiated by reaction of the active serine of the protease with the
reactive centre of the serpin. This cleaves the reactive centre, which then
moves 71 A to the opposite pole of the serpin, taking the tethered protease with
it. The tight linkage of the two molecules and resulting overlap of their
structures does not affect the hyperstable serpin, but causes a surprising 37%
loss of structure in the protease. This is induced by the plucking of the serine
from its active site, together with breakage of interactions formed during
zymogen activation. The disruption of the catalytic site prevents the release of
the protease from the complex, and the structural disorder allows its
proteolytic destruction. It is this ability of the conformational mechanism to
crush as well as inhibit proteases that provides the serpins with their
selective advantage.
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Figure 1.
Figure 1: Formation of the complex. Ribbon depictions of
native  [1]-antitrypsin8
with trypsin aligned above it in the docking orientation (left),
and of the complex showing the 71 Å shift of the P1 methionine
of [1]-antitrypsin,
with full insertion of the cleaved reactive-centre loop into the
A-sheet (right). Regions of disordered structure in the
complexed trypsin are shown as interrupted coils projected from
the native structure of trypsin. Red, [1]-antitrypsin
 -sheet
A; yellow, reactive-centre loop; green ball-and-stick, P1 Met;
cyan, trypsin (with helices in magenta for orientation); red
ball-and-stick, active serine 195.
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Figure 2.
Figure 2: Proteolytic susceptibility of the complexed protease.
A stereo side view of the complex coloured according to C temperature
factors for trypsin ( [1]-antitrypsin,
coloured as in Fig. 1, retains the low B-factors of its isolated
cleaved form). The nine sites of proteolytic cleavage are shown
as balls and all occur in regions of crystallographic disorder
or high mobility. Cleavage sites: green, of trypsin, by
trypsin5; yellow, of chymotrypsin, by chymotrypsin 6; magenta,
of chymotrypsin, by neutrophil elastase^6. Temperature factors
from blue to red, going through green at 40 Å 2, yellow at 60 Å2
and red at 90 Å 2. When the full native trypsin structure is
superimposed on the ordered region of trypsin in the complex
there are no clashes with symmetry related molecules. The only
significant steric overlap is within the asymmetric unit between
the serpin and the disordered region of trypsin, as denoted here
by cyan balls.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2000,
407,
923-926)
copyright 2000.
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