Engineered Acetylcholine Binding Proteins for Structure-guided Design of Safer Insecticides

The nicotinic acetylcholine receptors (nAChRs) are the biological target of the fastest-growing class of insecticides worldwide — the neonicotinoids. This class of insecticide is known to affect off-target organisms, including humans and honey bees. The development of safer and more selective insecticides can be assisted by structure-based ligand design wherein one examines the atom-by-atom protein/ligand interactions. As the nAChRs are integral membrane proteins with each subunit containing 4 transmembrane spanning regions the ability to reliably generate X-ray crystal structures of sufficient resolution and quality remains elusive. This technical difficulty is compounded in the case of insect nAChRs in that there are extremely few reports of successful culturing of insect neurons or heterologous of insect nAChRs. To circumvent these challenges we utilize the soluble acetylcholine binding proteins (AChBPs) from Aplysia californica and Lymnaea stagnalis for structural characterization and relative binding...