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PDBsum entry 1f2a
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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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A target within the target: probing cruzain'S p1' Site to define structural determinants for the chagas' Disease protease.
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Authors
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L.S.Brinen,
E.Hansell,
J.Cheng,
W.R.Roush,
J.H.Mckerrow,
R.J.Fletterick.
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Ref.
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Structure, 2000,
8,
831-840.
[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 present in nearly
all groups of eukaryotes and play vital roles in a wide range of biological
processes and diseases, including antigen and hormone processing, bacterial
infection, arthritis, osteoporosis, Alzheimer's disease and cancer-cell
invasion. Because they are critical to the life-cycle progression of many
pathogenic protozoa, they represent potential targets for selective inhibitors.
Chagas' disease, the leading cause of death due to heart disease in Latin
American countries, is transmitted by Trypanosoma cruzi. Cruzain is the major
cysteine protease of T cruzi and has been the target of extensive
structure-based drug design. RESULTS: High-resolution crystal structures of
cruzain bound to a series of potent phenyl-containing vinyl-sulfone, sulfonate
and sulfonamide inhibitors have been determined. The structures show a
consistent mode of interaction for this family of inhibitors based on a covalent
Michael addition formed at the enzyme's active-site cysteine, hydrophobic
interactions in the S2 substrate-binding pocket and a strong constellation of
hydrogen bonding in the S1' region. CONCLUSIONS: The series of
vinyl-sulfone-based inhibitors examined in complex with cruzain was designed to
probe recognition and binding potential of an aromatic-rich region of the
enzyme. Analysis of the interactions formed shows that aromatic interactions
play a less significant role, whereas the strength and importance of hydrogen
bonding in the conformation adopted by the inhibitor upon binding to the enzyme
was highlighted. A derivative of one inhibitor examined is currently under
development as a therapeutic agent against Chagas' disease.
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Figure 6.
Figure 6. Surface representation of the cruzain active-site
region. Hydrophobic residues are indicated in green. (Note that
the sides of the S2 pocket are lined with hydrophobic patches.)
The surfaces of amino acids of interest (see text) are labeled
and color coded: Gln19 and His159, cyan; Asp158 and Ser139,
magenta; Cys25 and Met142, yellow. Inhibitor molecules are
displayed as sticks. (a) VSI, (b) VSII, (c) VSIII, (d) VSIV.
This figure was prepared with the program GRASP [44].
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2000,
8,
831-840)
copyright 2000.
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Secondary reference #1
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Title
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The crystal structure of cruzain: a therapeutic target for chagas' Disease.
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Authors
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M.E.Mcgrath,
A.E.Eakin,
J.C.Engel,
J.H.Mckerrow,
C.S.Craik,
R.J.Fletterick.
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Ref.
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J Mol Biol, 1995,
247,
251-259.
[DOI no: ]
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PubMed id
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Figure 2.
Figure 2. The alpha carbon trace
for cruzain (green) and papain (pink)
which have been optimally superim-
posed, is shown for the region of
the Cys153-Cys200 disulfide bond.
Neighboring insertions and del-
etions in the 2 proteins shift the
position of this conserved disulfide
bond. The side-chains for the cys-
teine residues are shown in yellow
and the catalytic triad is shown for
papain.
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Figure 3.
Figure 3. Equivalent view of the
cruzain (right) and papain (left) S2
substrate binding sites with Z-Phe-
Ala-FMK bound. The Z moiety has
been deleted to better show the
interactions made with the proteases
by Phe at P2 of the inhibitor. Atoms
of cruzain and papain are shown
with solvent accessible surfaces
while the inhibitor is shown as a solid
surface rendering in pink. There is a
60° rotation of the Phe side-chain in
cruzain relative to papain. The 5
residues which comprise S2 differ in
the 2 enzymes. Papain makes twice
as many van der Waals contacts with
Phe as cruzain does.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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