title: Identification, structural and pharmacological characterization of τ-CnVA, a conopeptide that selectively interacts with somatostatin sst3 receptor.
abstract: Conopeptides are a diverse array of small linear and reticulated peptides that interact with high potency and selectivity with a large diversity of receptors and ion channels. They are used by cone snails for prey capture or defense. Recent advances in venom gland transcriptomic and venom peptidomic/proteomic technologies combined with bioactivity screening approaches lead to the identification of new toxins with original pharmacological profiles. Here, from transcriptomic/proteomic analyses of the Conus consors cone snail, we identified a new conopeptide called τ-CnVA, which displays the typical cysteine framework V of the T1-conotoxin superfamily. This peptide was chemically synthesized and its three-dimensional structure was solved by NMR analysis and compared to that of TxVA belonging to the same family, revealing very few common structural features apart a common orientation of the intercysteine loop. Because of the lack of a clear biological function associated with the T-conotoxin family, τ-CnVA was screened against more than fifty different ion channels and receptors, highlighting its capacity to interact selectively with the somatostatine sst3 receptor. Pharmacological and functional studies show that τ-CnVA displays a micromolar (Ki of 1.5μM) antagonist property for the sst3 receptor, being currently the only known toxin to interact with this GPCR subfamily.
authors.affiliation: CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Laboratoire de Toxinologie Moléculaire et Biotechnologies, Gif-sur-Yvette, France.
authors.forename: C
authors.initials: C
authors.lastname: Petrel
authors.forename: H G
authors.initials: HG
authors.lastname: Hocking
authors.forename: M
authors.initials: M
authors.lastname: Reynaud
authors.forename: G
authors.initials: G
authors.lastname: Upert
authors.forename: Ph
authors.initials: P
authors.lastname: Favreau
authors.forename: D
authors.initials: D
authors.lastname: Biass
authors.forename: M
authors.initials: M
authors.lastname: Paolini-Bertrand
authors.forename: S
authors.initials: S
authors.lastname: Peigneur
authors.forename: J
authors.initials: J
authors.lastname: Tytgat
authors.forename: N
authors.initials: N
authors.lastname: Gilles
authors.forename: O
authors.initials: O
authors.lastname: Hartley
authors.forename: R
authors.initials: R
authors.lastname: Boelens
authors.forename: R
authors.initials: R
authors.lastname: Stocklin
authors.forename: D
authors.initials: D
authors.lastname: Servent
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020916:Conotoxins / Q000737:chemistry* / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D007473:Ion Channels / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D040901:Proteomics; D017481:Receptors, Somatostatin / Q000187:drug effects*; D059467:Transcriptome; D014982:Xenopus laevis
chemical_list: D020916:Conotoxins; D007473:Ion Channels; D017481:Receptors, Somatostatin; C582210:tau-conotoxin VA, Conus consors; D002118:Calcium