Crystal structures of allosamidin derivatives in complex with human macrophage chitinase
Crystal structures of allosamidin derivatives in complex with human macrophage chitinase
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DOI：
10.1074/jbc.m300362200
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发表时间：
2003-05-30
影响因子：
4.8
通讯作者：
van Aalten, DMF
中科院分区：
文献类型：
--
作者：
Rao, FV;Houston, DR;van Aalten, DMF
假三糖异胺苷是一种有效的18族几丁质酶抑制剂，具有抗昆虫、真菌和恶性疟原虫生命周期的生物活性。报道了几种衍生物的合成及其生物学性质。以前已经用x射线晶体学测定了异胺嘧啶与几种18族几丁质酶的结构相互作用。在这里，一个高分辨率结构的壳三醇苷酶，人类巨噬细胞几丁质酶，在复杂的allosamidin被提出。此外，还描述了allosamidin衍生物demethylallosamidin、methylallosamidin和glucoallosamidin B的配合物及其抑制特性。与其他几丁质酶类似，缺乏甲基的异胺嘧啶衍生物对人几丁质酶的抑制作用强10倍，而对甲基和C3表聚体衍生物的抑制作用较小。这些结构解释了在改变氢键和疏水相互作用方面对抑制的影响，连同移位的水分子。这里报道的数据代表了基于结构设计特异性异胺嘧啶衍生物的第一步。
The pseudotrisaccharide allosamidin is a potent family 18 chitinase inhibitor with demonstrated biological activity against insects, fungi, and the Plasmodium falciparum life cycle. The synthesis and biological properties of several derivatives have been reported. The structural interactions of allosamidin with several family 18 chitinases have been determined by x-ray crystallography previously. Here, a high resolution structure of chitotriosidase, the human macrophage chitinase, in complex with allosamidin is presented. In addition, complexes of the allosamidin derivatives demethylallosamidin, methylallosamidin, and glucoallosamidin B are described, together with their inhibitory properties. Similar to other chitinases, inhibition of the human chitinase by allosamidin derivatives lacking a methyl group is 10-fold stronger, and smaller effects are observed for the methyl and C3 epimer derivatives. The structures explain the effects on inhibition in terms of altered hydrogen bonding and hydrophobic interactions, together with displaced water molecules. The data reported here represent a first step toward structure-based design of specific allosamidin derivatives.