Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant.
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.
Celie
Patrick H N
PH
Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Kasheverov
Igor E
IE
Mordvintsev
Dmitry Y
DY
Hogg
Ronald C
RC
van Nierop
Pim
P
van Elk
René
R
van Rossum-Fikkert
Sarah E
SE
Zhmak
Maxim N
MN
Bertrand
Daniel
D
Tsetlin
Victor
V
Sixma
Titia K
TK
Smit
August B
AB
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
C428944:AChBP protein, Lymnaea; D002352:Carrier Proteins; D020916:Conotoxins; D046912:Multiprotein Complexes; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; C089038:alpha-conotoxin PnIA