Shi Mingyu, Zhang Shuhao, Zhu Angqi, Toyoda Yosuke, Kong Fang, Sun Xiaoou, Xu Xinyu, Yan Chuangye, Liu Xiangyu
State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
School of Medicine, Tsinghua University, Beijing, China.
Commun Biol. 2025 Jul 16;8(1):1055. doi: 10.1038/s42003-025-08405-0.
There is growing interest in peptide or small protein based drugs targeting G protein-coupled receptors (GPCRs) for improved subtype selectivity over small molecules. Naturally occurring toxins represent rich sources of such ligands. AdTx1 (ρ-Da1a), a three-finger toxin (3FTx) from the green Mamba Snake, selectively binds and antagonizes α-adrenoceptors. Here, we present the cryo-electron microscopy structure of α-adrenoceptor in complex with AdTx1. The structure reveals the molecular mechanism of the subtype selectivity and antagonist activity of AdTx1 for α-adrenoceptor, which is different from those revealed by the only 3FTx-GPCR structure reported so far, the Muscarinic toxins 7 (MT7) - Muscarinic acetylcholine receptor 1 (MAChR) structure. Based on the structural information, we further engineered the AdTx1 and enhanced its antagonist activity by introducing three mutations. The results highlight the potential of developing potent toxin drugs towards GPCRs based on the 3FTx scaffold and structural information.
人们对基于肽或小蛋白的药物越来越感兴趣，这类药物靶向G蛋白偶联受体（GPCR），以提高相对于小分子的亚型选择性。天然存在的毒素是此类配体的丰富来源。AdTx1（ρ-Da1a）是一种来自绿曼巴蛇的三指毒素（3FTx），它能选择性地结合并拮抗α-肾上腺素能受体。在此，我们展示了与AdTx1复合的α-肾上腺素能受体的冷冻电子显微镜结构。该结构揭示了AdTx1对α-肾上腺素能受体的亚型选择性和拮抗活性的分子机制，这与迄今为止报道的唯一3FTx-GPCR结构——毒蕈碱毒素7（MT7）-毒蕈碱型乙酰胆碱受体1（MAChR）结构所揭示的机制不同。基于这些结构信息，我们进一步对AdTx1进行改造，并通过引入三个突变增强了其拮抗活性。结果突出了基于3FTx支架和结构信息开发针对GPCR的强效毒素药物的潜力。
