Chen Qi, Chen Wei, Kumar Ashutosh, Jiang Xi, Janezic Matej, Zhang Kam Y J, Yang Qing
State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa 230-0045, Japan.
J Agric Food Chem. 2021 Mar 24;69(11):3519-3526. doi: 10.1021/acs.jafc.1c00162. Epub 2021 Mar 10.
Nematode chitinases play crucial roles in various processes of the nematode lifecycle, including hatching, molting, and reproduction. Small-molecule inhibitors of nematode chitinases have shown promise for controlling nematode pests. However, the lack of structural information makes it a challenge to develop nematicides targeting nematode chitinases. Here, we report the first crystal structure of a representative nematode chitinase, that of Cht1 from the model nematode , to a 1.7 Å resolution. Cht1 is a highly conserved chitinase among nematodes, and structural comparison with other chitinases revealed that Cht1 has a classical TIM-barrel fold with some subtle structural differences in the substrate-binding cleft. Benefiting from the obtained crystal structure, we identified a series of novel inhibitors by hierarchical virtual screening. Analysis of the structure-activity relationships of these compounds provided insight into their interactions with the enzyme active site, which may inform future work in improving the potencies of their inhibitory activities. This work gives an insight into the structural features of nematode chitinases and provides a solid basis for the development of inhibitors.
线虫几丁质酶在包括孵化、蜕皮和繁殖在内的线虫生命周期的各个过程中发挥着关键作用。线虫几丁质酶的小分子抑制剂已显示出控制线虫害虫的前景。然而，缺乏结构信息使得开发针对线虫几丁质酶的杀线虫剂成为一项挑战。在此，我们报告了一种代表性线虫几丁质酶（来自模式线虫的Cht1）的首个晶体结构，分辨率达到1.7 Å。Cht1是线虫中高度保守的几丁质酶，与其他几丁质酶的结构比较表明，Cht1具有经典的TIM桶状折叠结构，在底物结合裂隙处存在一些细微的结构差异。得益于所获得的晶体结构，我们通过分级虚拟筛选鉴定出了一系列新型抑制剂。对这些化合物构效关系的分析为它们与酶活性位点的相互作用提供了见解，这可能为未来提高其抑制活性效力的工作提供参考。这项工作深入了解了线虫几丁质酶的结构特征，并为抑制剂的开发提供了坚实基础。
