Nicotinic acetylcholine receptors (nAChRs) are members of the ligand-gated ion channel (LGIC) family that mediate and/or modulate synaptic signaling. They are members of the pharmaceutically important subfamily of pentameric ligand gated ion channels that includes GABAA, GABAC, 5HT3 serotonin, and glycine receptors. nAChRs play important roles in memory and learning processes and receptor alteration is thought to contribute to diseases including schizophrenia, Alzheimers disease, drug addiction. Moreover they play a determinant role in the autoimmune disease myasthenia gravis and have been associated to nocturnal frontal lobe epilepsy. nAChRs are the prime mediators of nicotine addiction in tobacco smokers. Because nAChRs have prominent roles in disease of the nervous system, they have become major targets in drug discovery programs. nAChRs exist in subtypes with distinct physiological and pharmacology properties. The lack of detailed structural information about these receptors has hampered rational drug design. Structural information about the ligand-binding domains and the subunit interfaces has expanded upon discovery and crystallization of the water-soluble homologue of the ligand-binding domain of nicotinic receptors, the acetylcholine binding protein (AChBP)(1,2). The crystal structure of AChBP has become an established model for the extracellular domain of the pentameric LGICs and homology models have been generated to analyze receptor-ligand interactions. AChBP has pharmacological properties resembling those of the homomeric alpha-7 subtype, with weak affinity for acetylcholine and a 10-fold higher affinity for nicotine. The ligand binding site of AChBP is characterized by the presence of aromatic and hydrophobic residues that are contributed by two adjacent subunits. The crystal structures of AChBP in complex with nicotine and carbamylcholine (3) have elucidated the molecular contacts between ligand and protein and are in excellent agreement with biochemical data obtained from nAChR binding studies. AChBP in complex with the nAChR agonists carbamylcholine and nicotine has revealed that both ligands bind at the same position and cause similar local conformational changes within the protein. These structures are useful tools for the development of new drugs for the nicotinic acetylcholine receptor and its family members. In addition to this, we determined the 2.4 Å structure of α-Conotoxin PnIA (A10L D14K), a potent blocker of the α7 nAChR, which binds with high affinity to Aplysia californica AChBP (Ac-AChBP)(4). 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. Moreover we revealed the 2.2- Å crystal structure of Ac-AChBP in complex with alpha-conotoxin ImI (5). This toxin also forms interactions in the ligand-binding site that were not seen in the complex of Ac-AChBP with PnIA(A10L D14K). In contrast to ImI, conotoxin PnIA(A10L D14K) lacks binding selectivity to AChBP homologs. The knowledge of these toxin-AChBP contacts will advance rationalized design of ligands using the Ctx framework and may lead to compounds with increased receptor subtype selectivity.