Crystal Structure of Lymnaeastagnalis Achbp Complexed with the Potent Nachr Antagonist Dhbe Suggests a Unique Mode of Antagonism

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Crystal Structure of Lymnaea stagnalis AChBP Complexed with the Potent nAChR Antagonist DHb E Suggests a Unique Mode of Antagonism
Azadeh Shahsavar1, Jette S. Kastrup1, Elsebet Ø. Nielsen2, Jesper L. Kristensen1, Michael Gajhede1, Thomas Balle1*¤
1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, 2 NeuroSearch A/S, Ballerup, Denmark

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-b-erythroidine (DHbE), which is a potent competitive antagonist of nAChRs. The structure reveals that binding of DHbE 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 DHbE may antagonize the receptor via a different mechanism compared to prototypical antagonists and toxins.
Citation: Shahsavar A, Kastrup JS, Nielsen EØ, Kristensen JL, Gajhede M, et al. (2012) Crystal Structure of Lymnaea stagnalis AChBP Complexed with the Potent nAChR Antagonist DHbE Suggests a Unique Mode of…...

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