High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: Mimicry of carbohydrate substrate
High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: Mimicry of carbohydrate substrate
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DOI：
10.1073/pnas.132060599
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发表时间：
2002-07-09
影响因子：
11.1
通讯作者：
van Aalten, DMF
中科院分区：
文献类型：
--
作者：
Houston, DR;Shiomi, K;van Aalten, DMF
在过去的几年中，家族18几丁质酶已被验证为针对在其正常生命周期中含有几丁质或与几丁质相互作用的人类病原体的药物设计的潜在靶标。到目前为止，只有一种有效的几丁质酶抑制剂已被详细描述，假三糖allosamidin。然而，最近，两个有效的天然产物环戊肽几丁质酶抑制剂，argifin和argadin，被报道。在这里，我们描述了高分辨率的晶体结构，揭示了这些环肽与家族18几丁质酶的相互作用的细节。这些结构是碳水化合物加工酶与高亲和力肽基抑制剂的复合物的实例，并详细显示了肽主链和侧链如何模拟酶与壳寡糖的相互作用。与酶学表征一起，结构解释了为什么argadin显示出比allosamidin强一个数量级的抑制，而argifin显示出较弱的抑制。这些肽以显著不同的方式与几丁质酶结合，这可以解释抑制常数的差异。这两个复合物提供了一个基础的有效的几丁质酶抑制剂的结构为基础的设计，可通过标准的肽化学。
Over the past years, family 18 chitinases have been validated as potential targets for the design of drugs against human pathogens that contain or interact with chitin during their normal life cycles. Thus far, only one potent chitinase inhibitor has been described in detail, the pseudotrisaccharide allosamidin. Recently, however, two potent natural-product cyclopentapeptide chitinase inhibitors, argifin and argadin, were reported. Here, we describe high-resolution crystal structures that reveal the details of the interactions of these cyclopeptides with a family 18 chitinase. The structures are examples of complexes of a carbohydrate-processing enzyme with high-affinity peptide-based inhibitors and show in detail how the peptide backbone and side chains mimic the interactions of the enzyme with chitooligosaccharides. Together with enzymological characterization, the structures explain why argadin shows an order of magnitude stronger inhibition than allosamidin, whereas argifin shows weaker inhibition. The peptides bind to the chitinase in remarkably different ways, which may explain the differences in inhibition constants. The two complexes provide a basis for structure-based design of potent chitinase inhibitors, accessible by standard peptide chemistry.