TY  - JOUR
A1  - Houston, Douglas R.
A1  - Shiomi, Kazuro
A1  - Arai, Noriko
A1  - Omura, Satoshi
A1  - Peter, Martin G.
A1  - Turberg, Andreas
A1  - Synstad, Bjoenar
A1  - Eijsink, Vincent G. H.
A1  - Van Aalten, Daan M. F.
T1  - High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors : mimicry of carbohydrate substrate
N2  - Over the past years, family 18 chitinases have been validated as potential targets for the design of drugs against human pathogens that contain or interact with chitin during their normal life cycles. Thus far, only one potent chitinase inhibitor has been described in detail, the pseudotrisaccharide allosamidin. Recently, however, two potent natural-product cyclopentapeptide chitinase inhibitors, argifin and argadin, were reported. Here, we describe high- resoln. crystal structures that reveal the details of the interactions of these cyclopeptides with a family 18 chitinase. The structures are examples of complexes of a carbohydrate-processing enzyme with high-affinity peptide-based inhibitors and show in detail how the peptide backbone and side chains mimic the interactions of the enzyme with chitooligosaccharides. Together with enzymol. characterization, the structures explain why argadin shows an order of magnitude stronger inhibition than allosamidin, whereas argifin shows weaker inhibition. The peptides bind to the chitinase in remarkably different ways, which may explain the differences in inhibition consts. The two complexes provide a basis for structure-based design of potent chitinase inhibitors, accessible by std. peptide chem.
Y1  - 2002
ER  -