Molecular Characterization of Binding Loop E in the Nematode Cys-Loop GABA Receptor.

摘要: Nematodes exhibit a vast array of cys-loop ligand-gated ion channels with unique pharmacologic characteristics. However, many the structural components that govern binding various ligands are unknown. The nematode GABA receptor uncoordinated 49 (UNC-49) is an important found at neuromuscular junctions plays role in sinusoidal movement worms. features this suggest there differences agonist site when compared mammalian receptors. In study, we examined each amino acid one main loops (loop E) via substituted cysteine accessibility method (SCAM) and analyzed interaction residues by molecular dynamic simulations. We 18 loop E mutants analyzed, H142C, R147C, S157C had significant changes EC 50 were accessible to modification methanethiosulfonate reagent (MTSET) resulting change I . addition, residue H142, which UNC-49 receptors, appears play negative sensitivity as its mutation increased caused partial 5-aminovaleric (DAVA) behave full agonist. Overall, study has revealed potential pocket between receptors could be exploited design novel anthelmintics.