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==Overview== | ==Overview== | ||
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-resolution 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 ... | 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-resolution 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 enzymological 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 constants. The two complexes provide, a basis for structure-based design of potent chitinase inhibitors, accessible by standard peptide chemistry. | ||
==About this Structure== | ==About this Structure== | ||
1H0G is a | 1H0G is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Serratia_marcescens Serratia marcescens] with ACE and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Hydrolase Hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.14. 3.2.1.14.] Structure known Active Site: GB1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1H0G OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: inhibitor]] | [[Category: inhibitor]] | ||
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Revision as of 14:29, 5 November 2007
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COMPLEX OF A CHITINASE WITH THE NATURAL PRODUCT CYCLOPENTAPEPTIDE ARGADIN FROM CLONOSTACHYS
OverviewOverview
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-resolution 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 enzymological 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 constants. The two complexes provide, a basis for structure-based design of potent chitinase inhibitors, accessible by standard peptide chemistry.
About this StructureAbout this Structure
1H0G is a Protein complex structure of sequences from Serratia marcescens with ACE and GOL as ligands. Active as Hydrolase, with EC number 3.2.1.14. Structure known Active Site: GB1. Full crystallographic information is available from OCA.
ReferenceReference
High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: mimicry of carbohydrate substrate., Houston DR, Shiomi K, Arai N, Omura S, Peter MG, Turberg A, Synstad B, Eijsink VG, van Aalten DM, Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9127-32. Epub 2002 Jul 1. PMID:12093900
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