Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHβE suggests a unique mode of antagonism
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....
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Published in | PloS one Vol. 7; no. 8; p. e40757 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
22.08.2012
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: AS JSK JLK MG TB. Performed the experiments: AS EØN. Analyzed the data: AS JSK EØN MG TB. Contributed reagents/materials/analysis tools: JLK. Wrote the paper: AS JSK TB. Competing Interests: EØN is employed by the company NeuroSearch A/S. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. Current address: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia |
ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0040757 |