2A3C

Crystal structure of Aspergillus fumigatus chitinase B1 in complex with pentoxifylline

Summary for 2A3C

• Entry DOI: 10.2210/pdb2a3c/pdb
• Related: 1W9P 1W9U 1W9V 2A3A 2A3B 2A3E
• Descriptor: chitinase, SULFATE ION, 3,7-DIMETHYL-1-(5-OXOHEXYL)-3,7-DIHYDRO-1H-PURINE-2,6-DIONE, ... (4 entities in total)
• Functional Keywords: (beta-alpha)8 barrel, chitinase-pentoxifylline complex, hydrolase
• Biological source: Aspergillus fumigatus
• Cellular location: Secreted : Q873X9
• Total number of polymer chains: 2
• Total formula weight: 97109.34

Authors

Rao, F.V.,Andersen, O.A.,Vora, K.A.,DeMartino, J.A.,van Aalten, D.M.F. (deposition date: 2005-06-24, release date: 2005-09-27, Last modification date: 2023-10-25)

Primary citation

Rao, F.V.,Andersen, O.A.,Vora, K.A.,Demartino, J.A.,van Aalten, D.M.
Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes.
Chem.Biol., 12:973-980, 2005

PubMed Abstract: Family 18 chitinases play key roles in a range of pathogenic organisms and are overexpressed in the asthmatic lung. By screening a library of marketed drug molecules, we have identified methylxanthine derivatives as possible inhibitor leads. These derivatives, theophylline, caffeine, and pentoxifylline, are used therapeutically as antiinflammatory agents, with pleiotropic mechanisms of action. Here it is shown that they are also competitive inhibitors against a fungal family 18 chitinase, with pentoxifylline being the most potent (K(i) of 37 microM). Crystallographic analysis of chitinase-inhibitor complexes revealed specific interactions with the active site, mimicking the reaction intermediate analog, allosamidin. Mutagenesis identified the key active site residues, conserved in mammalian chitinases, which contribute to inhibitor affinity. Enzyme assays also revealed that these methylxanthines are active against human chitinases.

PubMed: 16183021
DOI: 10.1016/j.chembiol.2005.07.009

Experimental method

X-RAY DIFFRACTION (2.07 Å)