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PDBsum entry 1mir
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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 of rat procathepsin b: model for inhibition of cysteine protease activity by the proregion.
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Authors
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M.Cygler,
J.Sivaraman,
P.Grochulski,
R.Coulombe,
A.C.Storer,
J.S.Mort.
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Ref.
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Structure, 1996,
4,
405-416.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Cysteine proteases of the papain superfamily are synthesized as
inactive precursors with a 60-110 residue N-terminal prosegment. The propeptides
are potent inhibitors of their parent proteases. Although the proregion binding
mode has been elucidated for all other protease classes, that of the cysteine
proteases remained elusive. RESULTS: We report the three-dimensional structure
of rat procathepsin B, determined at 2.8 A resolution. The 62-residue proregion
does not form a globular structure on its own, but folds along the surface of
mature cathepsin B. The N-terminal part of the proregion packs against a surface
loop, with Trp24p (p indicating the proregion) playing a pivotal role in these
interactions. Inhibition occurs by blocking access to the active site: part of
the proregion enters the substrate-binding cleft in a similar manner to a
natural substrate, but in a reverse orientation. CONCLUSIONS: The structure of
procathepsin B provides the first insight into the mode of interaction between a
mature cysteine protease from the papain superfamily and its prosegment.
Maturation results in only one loop of cathepsin B changing conformation
significantly, replacing contacts lost by removal of the prosegment. Contrary to
many other proproteases, no rearrangement of the N terminus occurs following
activation. Binding of the prosegment involves interaction with regions of the
enzyme remote from the substrate-binding cleft and suggests a novel strategy for
inhibitor design. The region of the prosegment where the activating cleavage
occurs makes little contact with the enzyme, leading to speculation on the
activation mechanism.
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Figure 2.
Figure 2. Molecular surface of the mature portion of
procathepsin B with the prosegment shown as a worm
representation. The view is toward the active site. Figure 2.
Molecular surface of the mature portion of procathepsin B with
the prosegment shown as a worm representation. The view is
toward the active site. (The figure was prepared using GRASP
[[3]48].)
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Figure 5.
Figure 5. Contacts between the prosegment and catB within the
occluding-loop crevice. Hydrogen bonds are shown as dashed
lines. The prosegment is drawn in dark lines. Figure 5.
Contacts between the prosegment and catB within the
occluding-loop crevice. Hydrogen bonds are shown as dashed
lines. The prosegment is drawn in dark lines. (Figure was
created using MOLSCRIPT [[3]47].)
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The above figures are
reprinted
by permission from Cell Press:
Structure
(1996,
4,
405-416)
copyright 1996.
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Secondary reference #1
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Title
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Crystallization of rat procathepsin b
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Authors
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J.Sivaraman,
R.Coulombe,
M.-C.Magny,
P.Mason,
J.S.Mort,
M.Cygler.
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Ref.
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TO BE PUBLISHED ...
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