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 () and Yuyong Tao ()
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Yixuan Zhong: University of Science and Technology of China
Huihui Tao: University of Science and Technology of China
Yu Zhang: University of Science and Technology of China
Binbin He: University of Science and Technology of China
Haizhan Jiao: The Chinese University of Hong Kong
Dandan Wang: University of Science and Technology of China
Maikun Teng: University of Science and Technology of China
Hongli Hu: The Chinese University of Hong Kong
Qiong Guo: University of Science and Technology of China
Yuyong Tao: University of Science and Technology of China

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61695-0

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