Structure-guided engineering of snake toxins for selective modulation of adrenergic and muscarinic receptors
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 c...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61695-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | 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. |
|---|---|
| ISSN: | 2041-1723 |