2XVP

ChiA1 from Aspergillus fumigatus, apostructure

Summary for 2XVP

• Entry DOI: 10.2210/pdb2xvp/pdb
• Related: 2XTK 2XUC 2XVN
• Descriptor: CLASS III CHITINASE CHIA1, PHOSPHATE ION (3 entities in total)
• Functional Keywords: hydrolase, gh18, tim barrel, aspergillosis
• Biological source: ASPERGILLUS FUMIGATUS
• Total number of polymer chains: 2
• Total formula weight: 69123.52

Authors

Schuettelkopf, A.W.,van Aalten, D.M.F. (deposition date: 2010-10-27, release date: 2011-06-01, Last modification date: 2024-10-09)

Primary citation

Rush, C.L.,Schuettelkopf, A.W.,Hurtado-Guerrero, R.,Blair, D.E.,Ibrahim, A.F.M.,Desvergnes, S.,Eggleston, I.M.,Van Aalten, D.M.F.
Natural Product-Guided Discovery of a Fungal Chitinase Inhibitor.
Chem.Biol., 17:1275-, 2010

PubMed Abstract: Natural products are often large, synthetically intractable molecules, yet frequently offer surprising inroads into previously unexplored chemical space for enzyme inhibitors. Argifin is a cyclic pentapeptide that was originally isolated as a fungal natural product. It competitively inhibits family 18 chitinases by mimicking the chitooligosaccharide substrate of these enzymes. Interestingly, argifin is a nanomolar inhibitor of the bacterial-type subfamily of fungal chitinases that possess an extensive chitin-binding groove, but does not inhibit the much smaller, plant-type enzymes from the same family that are involved in fungal cell division and are thought to be potential drug targets. Here we show that a small, highly efficient, argifin-derived, nine-atom fragment is a micromolar inhibitor of the plant-type chitinase ChiA1 from the opportunistic pathogen Aspergillus fumigatus. Evaluation of the binding mode with the first crystal structure of an A. fumigatus plant-type chitinase reveals that the compound binds the catalytic machinery in the same manner as observed for argifin with the bacterial-type chitinases. The structure of the complex was used to guide synthesis of derivatives to explore a pocket near the catalytic machinery. This work provides synthetically tractable plant-type family 18 chitinase inhibitors from the repurposing of a natural product.

PubMed: 21168763
DOI: 10.1016/J.CHEMBIOL.2010.07.018

Experimental method

X-RAY DIFFRACTION (2 Å)