Crystal Structure of Lymnaea stagnalis AChBP Complexed with the Potent nAChR Antagonist DHßE Suggests a Unique Mode of Antagonism
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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-ß-erythroidine (DHßE), which is a potent competitive antagonist of nAChRs. The structure reveals that binding of DHßE 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 DHßE may antagonize the receptor via a different mechanism compared to prototypical antagonists and toxins.
Original language | English |
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Journal | P L o S One |
Volume | 7 |
Issue number | 8 |
Pages (from-to) | e40757 |
ISSN | 1932-6203 |
DOIs | |
Publication status | Published - 2012 |
ID: 40766378