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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-03, Vol.283 (11), p.7100-7108
Main Authors: Dutertre, Sébastien, Croker, Daniel, Daly, Norelle L., Andersson, Åsa, Muttenthaler, Markus, Lumsden, Natalie G., Craik, David J., Alewood, Paul F., Guillon, Gilles, Lewis, Richard J.
Format: Article
Language:English
Subjects:
Animals
Chemical Sciences
CHO Cells
Conus Snail - metabolism
Conus tulipa
Cricetinae
Cricetulus
Humans
Inositol Phosphates - chemistry
Life Sciences
Marine
Medicinal Chemistry
Models, Biological
Oxytocin - analogs & derivatives
Oxytocin - chemistry
Oxytocin - metabolism
Peptides - chemistry
Receptors, Oxytocin - chemistry
Receptors, Vasopressin - chemistry
Toxicology
Vasopressins - chemistry
Vasotocin - chemistry
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Summary: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 V1a receptor. All peptides in this family contain two conserved amino acids within the exocyclic tripeptide (Pro7 and Gly9), which are replaced with Leu7 and Val9 in conopressin-T. Whereas conopressin-T binds only to OT and V1a receptors, an L7P analogue had increased affinity for the V1a receptor and weak V2 receptor binding. Surprisingly, replacing Gly9 with Val9 in OT and vasopressin revealed that this position can function as an agonist/antagonist switch at the V1a 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 V1a receptor.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M706477200