Biomedical Engineering Reference
All crystal structures of plasmepsins, including those discussed later in this
narrative, were found to exist as either dimers or tetramers in the crystal-
lographic asymmetric unit. 28 This raised the question of whether the enzymes
act as dimers in cells during their degradative activities. Liu et al. 32 studied this
point by using gel filtration, site-directed mutagenesis, and ultracentrifugation,
and found that PMII exists as a monomer, which exhibits full activity.
Further details on the structure of PfPMII in complex with inhibitors were
provided by Asojo et al. 33,34 . In particular, the 2003 paper made the interesting
point that larger inhibitors may be accommodated at the active site cavity when
some enzyme groups rotate to provide additional binding space. Thus, the
enzyme is providing a type of adaptability that had heretofore not been
observed; subsequent studies with a number of systems have verified that this is
a common occurrence. 35
Liu et al. 25 described the analysis of a series of peptide-based inhibitors and
reported on the X-ray structure of one of these bound to plasmepsin II. This
structure is mentioned here because it shows the binding of a structure in
exactly the way that a peptide substrate would interact with the active site.
Thus, the amino acids along the sequence fill in the various subsites along the
active site cleft. This structure provides excellent clues for the design of more
potent inhibitors. The development of these inhibitors and additional analysis
will be discussed in a later section of this chapter (Figure 11.3).
The excellent review by Bhaumik et al. 28 gives a complete list of the known
structures determined for plasmepsins. Khazanovich-Bernstein et al. reported
on the structure of the semi-proplasmepsin II in the first report on a zymogen
Figure 11.3 Binding of a peptidomimetic inhibitor into the active site of plasmepsin II
(PDB: 2R9B, Liu et al. 25 ). The eight amino acid inhibitor can be seen to
stretch out through the active site cleft from the amino terminus on the
left hand side to the carboxyl terminus on the right hand side. This is
termed the ''canonical'' binding mode and is seen in most cases of ligand
binding in the active site of the aspartic proteinase class of enzyme. The
amino acid side chains of the inhibitor make strong contacts within the
active site cleft in exactly the same way that a substrate would.