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 (Pro7 and Gly9), which are replaced with Leu7 and Val9 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 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 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.
Dutertre
Sébastien
S
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Croker
Daniel
D
Daly
Norelle L
NL
Andersson
Asa
A
Muttenthaler
Markus
M
Lumsden
Natalie G
NG
Craik
David J
DJ
Alewood
Paul F
PF
Guillon
Gilles
G
Lewis
Richard J
RJ
D000818:Animals; D016466:CHO Cells; D052078:Conus Snail / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry; D008954:Models, Biological; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D018045:Receptors, Oxytocin / Q000737:chemistry; D017483:Receptors, Vasopressin / Q000737:chemistry; D014667:Vasopressins / Q000737:chemistry*; D014668:Vasotocin / Q000737:chemistry
D007295:Inositol Phosphates; D010455:Peptides; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; C528960:conopressin-T, Conus tulipa; D014667:Vasopressins; D010121:Oxytocin; D014668:Vasotocin