title: Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant.
abstract: Conotoxins (Ctx) form a large family of peptide toxins from cone snail venoms that act on a broad spectrum of ion channels and receptors. The subgroup alpha-Ctx specifically and selectively binds to subtypes of nicotinic acetylcholine receptors (nAChRs), which are targets for treatment of several neurological disorders. Here we present the structure at a resolution of 2.4 A of alpha-Ctx PnIA (A10L D14K), a potent blocker of the alpha(7)-nAChR, bound with high affinity to acetylcholine binding protein (AChBP), the prototype for the ligand-binding domains of the nAChR superfamily. Alpha-Ctx is buried deep within the ligand-binding site and interacts with residues on both faces of adjacent subunits. The toxin itself does not change conformation, but displaces the C loop of AChBP and induces a rigid-body subunit movement. Knowledge of these contacts could facilitate the rational design of drug leads using the Ctx framework and may lead to compounds with increased receptor subtype selectivity.
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Patrick H N
authors.initials: PH
authors.lastname: Celie
authors.forename: Igor E
authors.initials: IE
authors.lastname: Kasheverov
authors.forename: Dmitry Y
authors.initials: DY
authors.lastname: Mordvintsev
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Hogg
authors.forename: Pim
authors.initials: P
authors.lastname: van Nierop
authors.forename: René
authors.initials: R
authors.lastname: van Elk
authors.forename: Sarah E
authors.initials: SE
authors.lastname: van Rossum-Fikkert
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Zhmak
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: Victor
authors.initials: V
authors.lastname: Tsetlin
authors.forename: Titia K
authors.initials: TK
authors.lastname: Sixma
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020916:Conotoxins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D003461:Crystallography; D004594:Electrophysiology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D018722:Nicotinic Agonists / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D012908:Snails / Q000737:chemistry*; D014981:Xenopus
chemical_list: C428944:AChBP protein, Lymnaea; D002352:Carrier Proteins; D020916:Conotoxins; D046912:Multiprotein Complexes; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; C089038:alpha-conotoxin PnIA