3ch9: Difference between revisions
No edit summary |
No edit summary |
||
| Line 14: | Line 14: | ||
'''Crystal structure of Aspergillus fumigatus chitinase B1 in complex with dimethylguanylurea''' | '''Crystal structure of Aspergillus fumigatus chitinase B1 in complex with dimethylguanylurea''' | ||
==Overview== | |||
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. | |||
==About this Structure== | ==About this Structure== | ||
3CH9 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3CH9 OCA]. | 3CH9 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3CH9 OCA]. | ||
==Reference== | |||
Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin., Andersen OA, Nathubhai A, Dixon MJ, Eggleston IM, van Aalten DM, Chem Biol. 2008 Mar;15(3):295-301. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18355729 18355729] | |||
[[Category: Aspergillus fumigatus]] | [[Category: Aspergillus fumigatus]] | ||
[[Category: Chitinase]] | [[Category: Chitinase]] | ||
| Line 28: | Line 34: | ||
[[Category: peptide inhibitor]] | [[Category: peptide inhibitor]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 2 11:32:51 2008'' | ||
Revision as of 11:32, 2 April 2008
| |||||||
| , resolution 2.20Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | , , , , , , , , , , , , , and | ||||||
| Ligands: | , | ||||||
| Gene: | chiB1 (Aspergillus fumigatus) | ||||||
| Activity: | Chitinase, with EC number 3.2.1.14 | ||||||
| Domains: | Glyco_18, Glyco_hydro_18 | ||||||
| Related: | 1W9V, 1W9P, 3CHC, 3CHD, 3CHE, 3CHF
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of Aspergillus fumigatus chitinase B1 in complex with dimethylguanylurea
OverviewOverview
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.
About this StructureAbout this Structure
3CH9 is a Single protein structure of sequence from Aspergillus fumigatus. Full crystallographic information is available from OCA.
ReferenceReference
Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin., Andersen OA, Nathubhai A, Dixon MJ, Eggleston IM, van Aalten DM, Chem Biol. 2008 Mar;15(3):295-301. PMID:18355729
Page seeded by OCA on Wed Apr 2 11:32:51 2008