9IQV

Cryo-EM structure of MT3-alpha1AAR

Summary for 9IQV

• Entry DOI: 10.2210/pdb9iqv/pdb
• EMDB information: 60796
• Descriptor: Muscarinic toxin 3, Alpha-1A adrenergic receptor,Soluble cytochrome b562 (2 entities in total)
• Functional Keywords: complex, membrane protein
• Biological source: Dendroaspis angusticeps (eastern green mamba); More
• Total number of polymer chains: 2
• Total formula weight: 56365.65

Authors

Zhong, Y.X.,Tao, H.H.,Tao, Y.Y. (deposition date: 2024-07-13, release date: 2025-07-23, Last modification date: 2026-02-04)

Primary citation

Zhong, Y.,Tao, H.,Zhang, Y.,He, B.,Jiao, H.,Wang, D.,Teng, M.,Hu, H.,Guo, Q.,Tao, Y.
Structure-guided engineering of snake toxins for selective modulation of adrenergic and muscarinic receptors.
Nat Commun, 16:6478-6478, 2025

PubMed 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 MAChR 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.

PubMed: 40659608
DOI: 10.1038/s41467-025-61695-0

Experimental method

ELECTRON MICROSCOPY (3.3 Å)