TY - JOUR
T1 - High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors
T2 - Mimicry of carbohydrate substrate
AU - Houston, Douglas R.
AU - Shiomi, Kazuro
AU - Arai, Noriko
AU - Omura, Satoshi
AU - Peter, Martin G.
AU - Turberg, Andreas
AU - Synstad, Bjørnar
AU - Eijsink, Vincent G.H.
AU - Van Aalten, Daan M.F.
PY - 2002/7/9
Y1 - 2002/7/9
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 inhibiors, argifin and argadin, were reported. Here, we describe high-resolution crystal structures that reveal the details of the interacions 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 enzymological characterization, the structures explain why argadin shows an order of magnitude stronger inhibition than allosamidin, whereas argifin shows weaker inhibition. The pepides bind to the chitinase in remarkably different ways, which may explain the differences in inhibition constants. The two complexes provide a basis for structure-based design of potent chitinase inhibitors, accessible by standard peptide chemistry.
AB - 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 inhibiors, argifin and argadin, were reported. Here, we describe high-resolution crystal structures that reveal the details of the interacions 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 enzymological characterization, the structures explain why argadin shows an order of magnitude stronger inhibition than allosamidin, whereas argifin shows weaker inhibition. The pepides bind to the chitinase in remarkably different ways, which may explain the differences in inhibition constants. The two complexes provide a basis for structure-based design of potent chitinase inhibitors, accessible by standard peptide chemistry.
UR - http://www.scopus.com/inward/record.url?scp=0037047120&partnerID=8YFLogxK
U2 - 10.1073/pnas.132060599
DO - 10.1073/pnas.132060599
M3 - Article
C2 - 12093900
AN - SCOPUS:0037047120
SN - 0027-8424
VL - 99
SP - 9127
EP - 9132
JO - Proceedings of the National Academy of Sciences (PNAS)
JF - Proceedings of the National Academy of Sciences (PNAS)
IS - 14
ER -