Conformational and receptor-binding properties of the insect neuropeptide proctolin and its analogues

Proctolin (Arg-Tyr-Leu-Pro-Thr) was the first insect neuropeptide to be chemically characterised. It plays an essential role in insect neurophysiology and is involved in muscular contraction and neuromodulation. Elements of secondary structure in solution have been studied by comparing data obtained from NMR and molecular dynamics simulations. Different secondary structural requirements are associated with agonist and antagonist activities. A favoured conformation of proctolin has an inverse gamma-turn, comprising an intramolecular hydrogen bond near the C-terminal end between Thr NH and Leu CO. Antagonists have a more compact structure resembling a 'paperclip' loop, containing an intramolecular hydrogen bond between Tyr NH and Pro CO, possibly stabilised by a salt bridge between the N- and C-terminal groups. A cyclic analogue retains antagonist activity and resembles a beta-bulge loop, also comprising intramolecular hydrogen bonds between Tyr NH and Pro CO and Thr CO. These models may offer feasible starting points for designing novel compounds with proctolinergic activity.