2XVN
A. fumigatus chitinase A1 phenyl-methylguanylurea complex
Summary for 2XVN
| Entry DOI | 10.2210/pdb2xvn/pdb |
| Related | 2XUC 2XVP |
| Descriptor | ASPERGILLUS FUMIGATUS CHITINASE A1, 1-METHYL-3-(N-PHENYLCARBAMIMIDOYL)UREA, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | hydrolase, inhibitor |
| Biological source | ASPERGILLUS FUMIGATUS |
| Total number of polymer chains | 3 |
| Total formula weight | 102274.54 |
| Authors | Rush, C.L.,Schuttelkopf, A.W.,Hurtado-Guerrero, R.,Blair, D.E.,Ibrahim, A.F.M.,Desvergnes, S.,Eggleston, I.M.,van Aalten, D.M.F. (deposition date: 2010-10-26, release date: 2010-11-03, Last modification date: 2024-10-23) |
| Primary citation | Rush, C.L.,Schuttelkopf, 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 Cited by 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: 21168763DOI: 10.1016/J.CHEMBIOL.2010.07.018 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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