Conopressin-T from Conus tulipa reveals an antagonist switch in vasopressin-like peptides

We report the discovery of conopressin-T, a novel bioactive peptide isolated from Conus tulipa venom. Conopressin-T belongs to the vasopressin- like peptide family and displays high sequence homology to the mammalian hormone oxytocin ( OT) and to vasotocin, the endogenous vasopressin analogue found in teleost fish, the cone snail's prey. Conopressin-T was found to act as a selective antagonist at the human V-1a receptor. All peptides in this family contain two conserved amino acids within the exocyclic tripeptide ( Pro(7) and Gly(9)), which are replaced with Leu(7) and Val(9) in conopressin-T. Whereas conopressin-T binds only to OT and V-1a receptors, an L7P analogue had increased affinity for the V-1a receptor and weak V-2 receptor binding. Surprisingly, replacing Gly(9) with Val(9) in OT and vasopressin revealed that this position can function as an agonist/ antagonist switch at the V-1a receptor. NMR structures of both conopressin-T and L7P analogue revealed a marked difference in the orientation of the exocyclic tripeptide that may serve as templates for the design of novel ligands with enhanced affinity for the V-1a receptor.