Lessons from nature: Structural studies and drug design driven by a homologous surrogate from invertebrates, AChBP

It has been almost 20 years since the discovery and crystallization of a structural surrogate, the Lymnaea stagnalis acetylcholine binding protein (Ls-AChBP), comprising the extracellular domain of the nicotinic acetylcholine receptors (nAChRs). Structural characterization of this soluble protein has increased our understanding of the requirements for agonist and antagonist interactions at the ligand recognition site of the nAChRs. Application can be extended to orthologs in the pentameric ligand-gated ion channel superfamily, encompassing receptors that depolarize or hyperpolarize upon neurotransmitter association. Despite the lack of transmembrane and intracellular motifs, the highly conserved binding or recognition loci have made these soluble binding proteins, and mutants derived from them, prototypic tools for molecular recognition and structural studies of pentameric ligand-gated ion channels. Targeting nAChRs has been a major goal as this family is associated with neurodegenerative diseases and disorders. Accordingly, the ligand binding site has played a key role to the development of selective ligands for modulation of this transmembrane proteins. In this review article, we cover both the potential and limitations of soluble surrogates, termed the AChBP family, in drug development. This article is part of the special issue on ‘Contemporary Advances in Nicotine Neuropharmacology’.