Abstract:
Anthelmintics are drugs used for controlling pathogenic helminths in animals and plants. The natural compound betaine and the recently developed synthetic compound monepantel are both anthelmintics that target the acetylcholine receptor ACR-23 and its homologs in nematodes. Here, we present cryo-electron microscopy structures of ACR-23 in apo, betaine-bound, and betaine- and monepantel-bound states. We show that ACR-23 forms a homo-pentameric channel, similar to some other pentameric ligand-gated ion channels (pLGICs). While betaine molecules are bound to the classical neurotransmitter sites in the inter-subunit interfaces in the extracellular domain, monepantel molecules are bound to allosteric sites formed in the inter-subunit interfaces in the transmembrane domain of the receptor. Although the pore remains closed in betaine-bound state, monepantel binding results in an open channel by wedging into the cleft between the transmembrane domains of two neighboring subunits, which causes dilation of the ion conduction pore. By combining structural analyses with site-directed mutagenesis, electrophysiology and in vivo locomotion assays, we provide insights into the mechanism of action of the anthelmintics monepantel and betaine.
Other ongoing works include working mechanism of other known or potential anthelmintics targets, exploration of potential new anthelmintics targets, and development of chemicals or protein modulators with nematode-killing activity.
Biography:
Dr. Qingfeng Chen was a postdoc at UTSW, focusing on the structure and function of mammalian ion channels. Now he is a PI at Yunnan University, and he is interested in how anthelmintics exert their nematode-killing effects via combined approaches of structure biology, electrophysiology, and locomotion assays. He is also actively pursuing drug discoveries targeting known or new drug targets.
