Conopressin-T fromConus tulipaReveals an Antagonist Switch in Vasopressin-like Peptides

Sébastien Dutertre, Daniel Croker, Norelle L. Daly, Åsa Andersson, Markus Muttenthaler, Natalie G. Lumsden, David J. Craik, Paul F. Alewood, Gilles Guillon, Richard J. Lewis
2008 Journal of Biological Chemistry  
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
more » ... yclic 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.
doi:10.1074/jbc.m706477200 pmid:18174156 fatcat:lacam5thtbcg5ljbj7llvelfb4