Structure of Saccharomyces cerevisiae chitinase 1 and screening-based discovery of potent inhibitors
Structure of Saccharomyces cerevisiae chitinase 1 and screening-based discovery of potent inhibitors
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DOI：
10.1016/j.chembiol.2007.03.015
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发表时间：
2007-05-01
影响因子：
--
通讯作者：
van Aalten, Daan M. F.
中科院分区：
文献类型：
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作者：
Hurtado-Guerrero, Ramon;van Aalten, Daan M. F.
几丁质酶水解几丁质的 β(1,4)-糖苷键，几丁质是真菌细胞壁的重要成分。真菌家族 18 几丁质酶的一个亚类的遗传数据表明其在细胞壁形态中发挥作用。这些酶的特异性抑制剂可用作研究它们在细胞壁形态发生中的作用的工具，并且可能具有抗真菌特性。在这里，我们描述了真菌“植物型”家族 18 几丁质酶（酿酒酵母 CTS1）的晶体结构。该酶对 4-甲基伞形基壳寡糖具有活性，并表现出异常低的最佳活性 pH 值。针对 ScCTS1 的文库筛选产生了 K-i 低至 3.2 μM 的命中结果。与三个系列的抑制剂复合的 ScCTS1 的晶体结构揭示了小芳香族部分对碳水化合物底物的惊人模仿，以及可以在这些抑制剂的优化中进一步利用的口袋。
Chitinases hydrolyse the beta(1,4)-glycosidic bonds of chitin, an essential fungal cell wall component. Genetic data on a subclass of fungal family 18 chitinases have suggested a role in cell wall morphology. Specific inhibitors of these enzymes would be useful as tools to study their role in cell wall morphogenesis and could possess antifungal properties. Here, we describe the crystallographic structure of a fungal "plant-type" family 18 chitinase, that of Saccharomyces cerevisiae CTS1. The enzyme is active against 4-methylumbelliferyl chitooligosaccharides and displays an unusually low pH optimum for activity. A library screen against ScCTS1 yielded hits with K-i's as low as 3.2 mu M. Crystal structures of ScCTS1 in complex with inhibitors from three series reveal striking mimicry of carbohydrate substrate by small aromatic moieties and a pocket that could be further exploited in optimization of these inhibitors.