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395 a.a.
Key reference
DOI no: 10.1016/j.chembiol.2004.10.013 Chem Biol 12:65-76 (2005) PubMed id: 15664516
Specificity and affinity of natural product cyclopentapeptide inhibitors against A. fumigatus, human, and bacterial chitinases. F.V.Rao, D.R.Houston, R.G.Boot, J.M.Aerts, M.Hodkinson, D.J.Adams, K.Shiomi, S.Omura, D.M.van Aalten. ABSTRACT
Family 18 chitinases play key roles in organisms ranging from bacteria to man. There is a need for specific, potent inhibitors to probe the function of these chitinases in different organisms. Such molecules could also provide leads for the development of chemotherapeuticals with fungicidal, insecticidal, or anti-inflammatory potential. Recently, two natural product peptides, argifin and argadin, have been characterized, which structurally mimic chitinase-chitooligosaccharide interactions and inhibit a bacterial chitinase in the nM-mM range. Here, we show that these inhibitors also act on human and Aspergillus fumigatus chitinases. The structures of these enzymes in complex with argifin and argadin, together with mutagenesis, fluorescence, and enzymology, reveal that subtle changes in the binding site dramatically affect affinity and selectivity. The data show that it may be possible to develop specific chitinase inhibitors based on the argifin/argadin scaffolds.
Selected figure(s)
Figure 1.
Figure 1. Chemical Structures of Argifin and ArgadinFigure 2.
Figure 2. Structure of AfChiB1The above figures are reprinted by permission from Cell Press: Chem Biol (2005, 12, 65-76) copyright 2005. Figures were selected by an automated process.
Literature references that cite this PDB file's key reference
PubMed id Reference
19109670 M.J.Dixon, A.Nathubhai, O.A.Andersen, D.M.van Aalten, and I.M.Eggleston (2009).
Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold.Org Biomol Chem, 7, 259-268.
19329983 T.Hirose, T.Sunazuka, A.Sugawara, A.Endo, K.Iguchi, T.Yamamoto, H.Ui, K.Shiomi, T.Watanabe, K.B.Sharpless, and S.Omura (2009).
Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry.J Antibiot (Tokyo), 62, 277-282.
19703025 V.Kairys, M.K.Gilson, V.Lather, C.A.Schiffer, and M.X.Fernandes (2009).
Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis.Chem Biol Drug Des, 74, 234-245.
18975073 Y.Lü, H.Yang, H.Hu, Y.Wang, Z.Rao, and C.Jin (2009).
Mutation of Trp137 to glutamate completely removes transglycosyl activity associated with the Aspergillus fumigatus AfChiB1.Glycoconj J, 26, 525-534.
18680214 C.Petter, C.Scholz, H.Wessner, G.Hansen, P.Henklein, T.Watanabe, and W.Höhne (2008).
Phage display screening for peptidic chitinase inhibitors.J Mol Recognit, 21, 401-409.
16844689 A.W.Schüttelkopf, O.A.Andersen, F.V.Rao, M.Allwood, C.Lloyd, I.M.Eggleston, and D.M.van Aalten (2006).
Screening-based discovery and structural dissection of a novel family 18 chitinase inhibitor.J Biol Chem, 281, 27278-27285.
PDB code: 2iuz
16193156 O.A.Andersen, M.J.Dixon, I.M.Eggleston, and D.M.van Aalten (2005).
Natural product family 18 chitinase inhibitors.Nat Prod Rep, 22, 563-579. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
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