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PDBsum entry 2a3a
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References listed in PDB file
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Key reference
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Title
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Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes.
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Authors
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F.V.Rao,
O.A.Andersen,
K.A.Vora,
J.A.Demartino,
D.M.Van aalten.
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Ref.
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Chem Biol, 2005,
12,
973-980.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
Figure 1. Characterization of Theophylline, Caffeine, and
Pentoxifylline Inhibition
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Figure 2.
Figure 2. Structures of the AfChiB1 Inhibitor Complexes
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2005,
12,
973-980)
copyright 2005.
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