title: New α-adrenergic property for synthetic MTβ and CM-3 three-finger fold toxins from black mamba.
abstract: Despite their isolation more than fifteen years ago from the venom of the African mamba Dendroaspis polylepis, very few data are known on the functional activity of MTβ and CM-3 toxins. MTβ was initially classified as a muscarinic toxin interacting non-selectively and with low affinity with the five muscarinic receptor subtypes while no biological function was determined for CM-3. Recent results highlight the multifunctional activity of three-finger fold toxins for muscarinic and adrenergic receptors and reveal some discrepancies in the pharmacological profiles of their venom-purified and synthetic forms. Here, we report the pharmacological characterization of chemically-synthesized MTβ and CM-3 toxins on nine subtypes of muscarinic and adrenergic receptors and demonstrate their high potency for α-adrenoceptors and in particular a sub-nanomolar affinity for the α1A-subtype. Strikingly, no or very weak affinity were found for muscarinic receptors, highlighting that pharmacological characterizations of venom-purified peptides may be risky due to possible contaminations. The biological profile of these two homologous toxins looks like that one previously reported for the Dendroaspis angusticeps ρ-Da1a toxin. Nevertheless, MTβ and CM-3 interact more potently than ρ-Da1a with α1B- and α1D-AR subtypes. A computational analysis of the stability of the MTβ structure suggests that mutation S38I, could be involved in this gain in function.
authors: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France; UFR Sciences de la Vie, Université Pierre et Marie Curie (UPMC), 4 place Jussieu, Paris, France.
authors: Guillaume
authors: G
authors: Blanchet
authors: Gregory
authors: G
authors: Upert
authors: Gilles
authors: G
authors: Mourier
authors: Bernard
authors: B
authors: Gilquin
authors: Nicolas
authors: N
authors: Gilles
authors: Denis
authors: D
authors: Servent
mesh_terms: D018663:Adrenergic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification; D000595:Amino Acid Sequence; D000818:Animals; D002942:Circular Dichroism; D017815:Elapidae; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011941:Receptors, Adrenergic / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D012910:Snake Venoms / Q000138:chemical synthesis / Q000737:chemistry*; D014118:Toxins, Biological / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification
chemical_list: D018663:Adrenergic Agents; D011941:Receptors, Adrenergic; D011976:Receptors, Muscarinic; D012910:Snake Venoms; D014118:Toxins, Biological
keywords: 2-(6-Chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate; Adrenergic toxin; Adrenoceptor; G-protein coupled receptor; GPCR; GPCRs; HCTU; MTs; Muscarinic receptor; Muscarinic toxin; N-methy-2-lpyrrolidone; N-methylmorpholine; N-methylscopolamine; NMM; NMP; NMS; Three-finger fold toxin; mAChRs; muscarinic acetylcholine receptors; muscarinic toxins