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Aspartoacylase
structure
The
structure of human brain aspartoacylase has been determined in complex with
a stable tetrahedral intermediate analog, N-phosphonomethyl-L-aspartate
(Le Coq, et al., 2008). This
potent inhibitor forms multiple interactions between each of its heteroatoms and the substrate binding groups arrayed
within the active site (Fig. 1). The binding of the catalytic intermediate
analog induces the conformational ordering of several substrate binding
groups thereby setting up the active site for catalysis.
Figure 1: The heteroatoms
of the intermediate are involved in multiple binding interactions with the
active site functional groups, with dashed lines showing each interactions
and the distances in Å listed. The active site mutants produced to examine
the role of these functional groups are shown in parentheses.
The highly ordered binding of this
inhibitor has allowed assignments to be made for substrate binding groups,
and provides strong support for a carboxypeptidase-type mechanism for the
hydrolysis of the amide bond of the substrate, N-acetyl-L-aspartate.
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Viola Research Group