Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHβE suggests a unique mode of antagonism

• Published in: PloS one Vol. 7; no. 8; p. e40757
• Main Authors: Shahsavar, Azadeh, Kastrup, Jette S, Nielsen, Elsebet Ø, Kristensen, Jesper L, Gajhede, Michael, Balle, Thomas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.08.2012; Public Library of Science (PLoS)
• Subjects: Acetylcholine receptors (nicotinic); Acetylcholine-binding protein; Allosteric properties; Animals; Biology; Competition; Crystal structure; Crystallography; Crystallography, X-Ray; Desensitization; Dihydro-beta-Erythroidine - chemistry; Dihydro-beta-Erythroidine - metabolism; Dihydro-beta-Erythroidine - pharmacology; Homology; Hydrogen Bonding; Ion channels; Ion channels (ligand-gated); Ligands; Lymnaea; Lymnaea stagnalis; Models, Molecular; Nicotine; Nicotinic Agonists - chemistry; Nicotinic Agonists - metabolism; Nicotinic Antagonists - chemistry; Nicotinic Antagonists - metabolism; Nicotinic Antagonists - pharmacology; Pharmacology; Physics; Protein Conformation; Proteins; Receptors; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - metabolism; Toxins; Denmark; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040757

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that belong to the Cys-loop receptor superfamily. These receptors are allosteric proteins that exist in different conformational states, including resting (closed), activated (open), and desensitized (closed) states. The acetylcholine binding protein (AChBP) is a structural homologue of the extracellular ligand-binding domain of nAChRs. In previous studies, the degree of the C-loop radial extension of AChBP has been assigned to different conformational states of nAChRs. It has been suggested that a closed C-loop is preferred for the active conformation of nAChRs in complex with agonists whereas an open C-loop reflects an antagonist-bound (closed) state. In this work, we have determined the crystal structure of AChBP from the water snail Lymnaea stagnalis (Ls) in complex with dihydro-β-erythroidine (DHβE), which is a potent competitive antagonist of nAChRs. The structure reveals that binding of DHβE to AChBP imposes closure of the C-loop as agonists, but also a shift perpendicular to previously observed C-loop movements. These observations suggest that DHβE may antagonize the receptor via a different mechanism compared to prototypical antagonists and toxins.