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PDBsum entry 3chc
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Hydrolase/hydrolase inhibitor
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PDB id
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3chc
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References listed in PDB file
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Key reference
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Title
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Structure-Based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin.
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Authors
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O.A.Andersen,
A.Nathubhai,
M.J.Dixon,
I.M.Eggleston,
D.M.Van aalten.
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Ref.
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Chem Biol, 2008,
15,
295-301.
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PubMed id
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Abstract
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Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides,
and antiasthmatics. Argifin, a natural product cyclopentapeptide, competitively
inhibits family 18 chitinases in the nanomolar to micromolar range and shows
extensive substrate mimicry. In an attempt to map the active fragments of this
large natural product, the cyclopentapeptide was progressively dissected down to
four linear peptides and dimethylguanylurea, synthesized using a combination of
solution and solid phase peptide synthesis. The peptide fragments inhibit
chitinase B1 from Aspergillus fumigatus (AfChiB1), the human chitotriosidase,
and chitinase activity in lung homogenates from a murine model of chronic
asthma, with potencies ranging from high nanomolar to high micromolar
inhibition. X-ray crystallographic analysis of the chitinase-inhibitor complexes
revealed that the conformations of the linear peptides were remarkably similar
to that of the natural product. Strikingly, the dimethylguanylurea fragment,
representing only a quarter of the natural product mass, was found to harbor all
significant interactions with the protein and binds with unusually high
efficiency. The data provide useful information that could lead to the
generation of drug-like, natural product-based chitinase inhibitors.
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