8ZFK

Caenorhabditis elegans ACR-23 in betaine and monepantel bound state

This is a non-PDB format compatible entry.

Summary for 8ZFK

• Entry DOI: 10.2210/pdb8zfk/pdb
• EMDB information: 60063
• Descriptor: Betaine receptor acr-23,Soluble cytochrome b562, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: ion channel, transport protein
• Biological source: Caenorhabditis elegans; More
• Total number of polymer chains: 5
• Total formula weight: 361219.19

Authors

Chen, Q.F.,Liu, F.L.,Li, T.Y.,Gong, H.H.,Guo, F.,Liu, S. (deposition date: 2024-05-08, release date: 2024-07-31, Last modification date: 2024-11-06)

Primary citation

Liu, F.,Li, T.,Gong, H.,Tian, F.,Bai, Y.,Wang, H.,Yang, C.,Li, Y.,Guo, F.,Liu, S.,Chen, Q.
Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23.
Embo J., 43:3787-3806, 2024

PubMed 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.

PubMed: 39009676
DOI: 10.1038/s44318-024-00165-7

Experimental method

ELECTRON MICROSCOPY (2.64 Å)