posted on 2021-03-11, 06:13authored byQi Chen, Wei Chen, Ashutosh Kumar, Xi Jiang, Matej Janezic, Kam Y. J. Zhang, Qing Yang
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 CeCht1 from the model nematode Caenorhabditis elegans, to a 1.7 Å resolution. CeCht1 is a highly conserved chitinase among nematodes,
and structural comparison with other chitinases revealed that CeCht1 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.