 |
PDBsum entry 1aim
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
1aim
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural determinants of specificity in the cysteine protease cruzain.
|
|
|
Authors
|
|
S.A.Gillmor,
C.S.Craik,
R.J.Fletterick.
|
|
|
Ref.
|
|
Protein Sci, 1997,
6,
1603-1611.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The structure of cruzain, an essential protease from the parasite Trypanosoma
cruzi, was determined by X-ray crystallography bound to two different covalent
inhibitors. The cruzain S2 specificity pocket is able to productively bind both
arginine and phenylalanine residues. The structures of cruzain bound to
benzoyl-Arg-Ala-fluoromethyl ketone and benzoyl-Tyr-Ala-fluoromethyl ketone at
2.2 and 2.1 A, respectively, show a pH-dependent specificity switch. Glu 205
adjusts to restructure the S2 specificity pocket, conferring right binding to
both hydrophobic and basic residues. Kinetic analysis of activated peptide
substrates shows that substrates placing hydrophobic residues in the specificity
pocket are cleaved at a broader pH range than hydrophilic substrates. These
results demonstrate how cruzain binds both basic and hydrophobic residues and
could be important for in vivo regulation of cruzain activity.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
The crystal structure of cruzain: a therapeutic target for chagas' Disease.
|
|
|
Authors
|
|
M.E.Mcgrath,
A.E.Eakin,
J.C.Engel,
J.H.Mckerrow,
C.S.Craik,
R.J.Fletterick.
|
|
|
Ref.
|
|
J Mol Biol, 1995,
247,
251-259.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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.
|
|
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.
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Elsevier
|
|
|
|
|
|
|
