Biomedical Engineering Reference
In-Depth Information
form of the plasmepsins. 36 While the overall features of the structure were
similar to the known aspartic peptidase family, one distinction was observed.
The prosegment sequence occupied a unique position in that it did not directly
block access to the active site as has been observed in structures of pepsinogen
and progastricsin. Rather, the prosegment of the truncated proplasmepsin II
interacted with the C-terminal domain, resulting in domain movement relative
to the N-terminal domain. This leads to separation of the two catalytic aspartic
acid residues, one of which is in either of the two domains, so that they are no
longer within hydrogen-bonding distance. Thus, the effect is to block catalytic
activity by perturbation of the catalytic site rather than directly blocking access
of substrate to the binding cleft. This type of proenzyme geometry was
observed again in the structure of the semi-proplasmepsin IV from P. vivax 37 as
well as in the semi-proenzyme of P. falciparum HAP (Figure 11.4). 28
The facile preparation of plasmepsin II also made this an excellent system to
investigate the role of various amino acids in the catalytic activity and in the
binding of inhibitors. Several groups studied these aspects of plasmepsin II in
an effort to help define the critical interactions that were present in inhibited
complexes. This information can lead to more precise design of inhibitors that
Figure 11.4
Structure of the proenzyme form of Plasmodium vivax PM 4. In this view,
the prosegment, a stretch of amino acids that are N-terminal to the
mature enzyme are seen with the side chains included in ''capped-stick''
representation. This view is provided to show that the prosegment does
NOT block access to the active site by binding within the cleft as happens
in the structures of pepsinogen and progastricsin, two other aspartic
proteinase proenzymes. In the case of PvPM 4, the prosegment wraps
around one domain of the enzyme, effectively pulling that domain away
from the other domain. This causes the separation between the two
catalytic aspartic acid residues, shown in space-filling representation in
this figure, to be separated by 6 A ˚ . Normally, the two catalytic aspartic
acids would be approximately 3 A ˚
apart and are thus able to hydrogen
bond to a bound water molecule.
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