title: Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHβE suggests a unique mode of antagonism.
abstract: 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.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Shahsavar
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
authors.forename: Elsebet Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004079:Dihydro-beta-Erythroidine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008195:Lymnaea; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D004079:Dihydro-beta-Erythroidine