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Structure-guided engineering of snake toxins for selective modulation of adrenergic and muscarinic receptors

Yixuan Zhong,Huihui Tao,Yu Zhang,Binbin He,Haizhan Jiao,Dandan Wang,Maikun Teng,Hongli Hu,Qiong Guo,Yuyong Tao

Published 2025 in Nature Communications

ABSTRACT

Adrenergic receptors (ARs) and muscarinic acetylcholine receptors (mAChRs) are essential G protein-coupled receptors (GPCRs) that regulate a wide range of physiological processes. Despite their significance, developing subtype-selective modulators for these receptors has been a formidable challenge due to the high structural and sequence similarities within their subfamilies. In this study, we elucidated the recognition and regulatory mechanisms of ARs and mAChRs by muscarinic toxin 3 (MT3), a cross-reactive ligand derived from snake venom. By leveraging the distinct toxin-receptor interfaces, we engineer a panel of toxin variants capable of selectively modulating α2A and M4AChR using computational design and directed evolution. These subtype-selective toxins not only provide valuable tools for basic research but also hold therapeutic potential for diseases associated with these GPCRs. This study further underscores the effectiveness of structure-guided approaches in transforming venom-derived scaffolds into receptor-specific modulators. Adrenergic and muscarinic receptors are key GPCRs involved in vital functions. Here, the authors engineer toxin variants that selectively target α2A and M4AChR, offering new tools and therapeutic leads through a structure-guided design strategy.

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