title: Polypharmacology profiles and phylogenetic analysis of three-finger toxins from mamba venom: case of aminergic toxins.
abstract: Composition of mamba's venom is quite atypical and characterized by the presence of a large diversity of three-finger fold toxins (3FTx) interacting with various enzymes, receptors and ion channels. In particular, 3FTx from mambas display the unique property to interact with class A GPCRs, sometimes with a high affinity and selectivity. A screening of five of these toxins (MT1, MT3, MT7, ρ-Da1a and ρ-Da1b) on 29 different subtypes of bioaminergic receptors, using competition binding experiments, highlights the diversity of their pharmacological profiles. These toxins may display either absolute selectivity for one receptor subtype or a polypharmacological property for various bioaminergic receptors. Nevertheless, adrenoceptor is the main receptor family targeted by these toxins. Furthermore, a new receptor target was identified for 3FTx and toxins in general, the ρ-Da1b interacting competitively with the human dopamine D3 receptor in the micromolar range. This result expands the diversity of GPCRs targeted by toxins and more generally highlights the multipotent interacting property of 3FTx. Phylogenic analyzes of these toxins show that muscarinic, adrenergic and dopaminergic toxins may be pooled in one family called aminergic toxins, this family coming probably from a specific radiation of ligands present in mamba venoms.
authors.affiliation: CEA, Institute of Biology and Technology (iBiTecS), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette 91191, France; UFR Sciences de la Vie, Université Pierre et Marie Curie (UPMC), 4 place Jussieu, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Blanchet
authors.affiliation: CEA, Institute of Biology and Technology (iBiTecS), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette 91191, France; CNRS, IRISA, Campus de Beaulieu, 35042 Rennes, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Collet
authors.affiliation: CEA, Institute of Biology and Technology (iBiTecS), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette 91191, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Mourier
authors.affiliation: CEA, Institute of Biology and Technology (iBiTecS), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette 91191, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gilles
authors.affiliation: CEA, Institute of Biology and Technology (iBiTecS), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette 91191, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Fruchart-Gaillard
authors.affiliation: CEA, Institute of Biology and Technology (iBiTecS), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette 91191, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Marcon
authors.affiliation: CEA, Institute of Biology and Technology (iBiTecS), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette 91191, France. Electronic address: denis.servent@cea.frCEA.
authors.forename: Denis
authors.initials: D
authors.lastname: Servent
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004546:Elapid Venoms / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D017815:Elapidae; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D064798:Polypharmacology; D017982:Receptors, Biogenic Amine / Q000378:metabolism*
chemical_list: D004546:Elapid Venoms; D017982:Receptors, Biogenic Amine
keywords: Aminergic toxins; GPCRs; Mamba venoms; Three-finger fold toxins