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Publication Abstract from PubMed

The anthelmintic paraherquamide A acts selectively on the nematode L-type nicotinic acetylcholine receptors (nAChRs) but the mechanism of its selectivity is unknown. This study targeted the basis of paraherquamide A selectivity by determining an X-ray crystal structure of the acetylcholine binding protein (AChBP), a surrogate nAChR ligand-binding domain, complexed with the compound and by measuring its actions on wild-type and mutant Caenorhabditis elegans nematodes and functionally expressed C. elegans nAChRs. Paraherquamide A showed a higher efficacy for the levamisole-sensitive (L-type (UNC-38/UNC-29/UNC-63/LEV8/LEV-1)) nAChR than the nicotine-sensitive (N-type (ACR-16)) nAChR, a result consistent with in vivo studies on wild type worms and worms with mutations in subunits of these two classes of receptors. The X-ray crystal structure of the Ls-AChBP-paraherquamide A complex and site-directed amino acid mutation studies showed for the first time that loop C, loop E and loop F of the orthosteric receptor binding site play critical roles in the observed L-type nAChR selective actions of paraherquamide A. Significance Statement Paraherquamide A, an oxindole alkaloid, has been shown to act selectively on the L-type over N-type nAChRs in nematodes, but the mechanism of selectivity is unknown. We have co-crystallized paraherquamide A with the acetylcholine binding protein, a surrogate of nAChRs, and found that structural features of loop C, loop E and loop F contribute to the L-type nAChR selectivity of the alkaloid. The results create a new platform for the design of anthelmintic drugs targeting cholinergic neurotransmission in parasitic nematodes.

Determinants of subtype-selectivity of the anthelmintic paraherquamide A on Caenorhabditis elegans nicotinic acetylcholine receptors.,Koizumi W, Otsubo S, Furutani S, Niki K, Takayama K, Fujimura S, Maekawa T, Koyari R, Ihara M, Kai K, Hayashi H, Ali MS, Kage-Nakadai E, Sattelle DB, Matsuda K Mol Pharmacol. 2023 Mar 22:MOLPHARM-AR-2022-000601. doi: , 10.1124/molpharm.122.000601. PMID:36948535^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.