7DJI

Crystal structure of Lymnaea stagnalis Acetylcholine binding protein (AChBP) complexed with Paraherquamide A

Summary for 7DJI

• Entry DOI: 10.2210/pdb7dji/pdb
• Descriptor: Acetylcholine-binding protein, Paraherquamide A, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: paraherquamide a, acetylcholine binding protein, nicotinic acetylcholine receptor, signaling protein
• Biological source: Lymnaea stagnalis (Great pond snail)
• Total number of polymer chains: 5
• Total formula weight: 124678.15

Authors

Ihara, M.,Matsuda, K. (deposition date: 2020-11-20, release date: 2021-11-24, Last modification date: 2024-10-23)

Primary citation

Koizumi, W.,Otsubo, S.,Furutani, S.,Niki, K.,Takayama, K.,Fujimura, S.,Maekawa, T.,Koyari, R.,Ihara, M.,Kai, K.,Hayashi, H.,Ali, M.S.,Kage-Nakadai, E.,Sattelle, D.B.,Matsuda, K.
Determinants of subtype-selectivity of the anthelmintic paraherquamide A on Caenorhabditis elegans nicotinic acetylcholine receptors.
Mol.Pharmacol., 2023

PubMed Abstract: 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 nematodes and functionally expressed nAChRs. Paraherquamide A showed a higher efficacy for the levamisole-sensitive [L-type (UNC-38/UNC-29/UNC-63/LEV-1/LEV-8)] 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 -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.

PubMed: 36948535
DOI: 10.1124/molpharm.122.000601

Experimental method

X-RAY DIFFRACTION (2.2 Å)