3CHC: Crystal Structure of Aspergillus Fumigatus Chitinase B1 in Complex With Monopeptide

Citation:
Abstract
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.
PDB ID: 3CHCDownload
MMDB ID: 63327
PDB Deposition Date: 2008/3/9
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 3CHC: monomeric; determined by author and by software (PISA)
Molecular Components in 3CHC
Label Count Molecule
Protein (1 molecule)
1
Chitinase
Molecule annotation
Chemicals (6 molecules)
1
1
2
5
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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