Blanchet Guillaume, Collet Guillaume, Mourier Gilles, Gilles Nicolas, Fruchart-Gaillard Carole, Marcon Elodie, Servent Denis
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.
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.
Biochimie. 2014 Aug;103:109-17. doi: 10.1016/j.biochi.2014.04.009. Epub 2014 May 1.
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.
曼巴蛇毒液的成分相当独特，其特点是存在大量与各种酶、受体和离子通道相互作用的三指折叠毒素（3FTx）。特别是，来自曼巴蛇的3FTx具有与A类G蛋白偶联受体（GPCR）相互作用的独特特性，有时具有高亲和力和选择性。通过竞争结合实验，对其中五种毒素（MT1、MT3、MT7、ρ-Da1a和ρ-Da1b）在29种不同亚型的生物胺能受体上进行筛选，突出了它们药理学特性的多样性。这些毒素可能对一种受体亚型表现出绝对选择性，或者对各种生物胺能受体具有多药理学特性。然而，肾上腺素能受体是这些毒素的主要靶向受体家族。此外，还为3FTx及一般毒素确定了一个新的受体靶点，ρ-Da1b在微摩尔范围内与人多巴胺D3受体竞争性相互作用。这一结果扩大了毒素靶向的GPCR的多样性，更普遍地突出了3FTx的多效相互作用特性。对这些毒素的系统发育分析表明，毒蕈碱能、肾上腺素能和多巴胺能毒素可能归为一个称为胺能毒素的家族，这个家族可能来自曼巴蛇毒液中特定的配体辐射。
