Structure and selectivity engineering of the M1muscarinic receptor toxin complex

Shoji Maeda, Jun Xu, Francois Marie N. Kadji, Mary J. Clark, Jiawei Zhao, Naotaka Tsutsumi, Junken Aoki, Roger K. Sunahara, Asuka Inoue, K. Christopher Garcia, Brian K. Kobilka

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Muscarinic toxins (MTs) are natural toxins produced by mamba snakes that primarily bind to muscarinic acetylcholine receptors (MAChRs) and modulate their function. Despite their similar primary and tertiary structures, MTs show distinct binding selectivity toward different MAChRs. The molecular details of how MTs distinguish MAChRs are not well understood. Here, we present the crystal structure of M1AChR in complex with MT7, a subtype-selective anti-M1AChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for M1AChR and the mechanism by which it regulates receptor function. Through in vitro engineering of MT7 finger regions that was guided by the structure, we have converted the selectivity from M1AChR toward M2AChR, suggesting that the three-finger fold is a promising scaffold for developing G protein-coupled receptor modulators.

Original languageEnglish
Pages (from-to)161-167
Number of pages7
JournalScience
Volume369
Issue number6500
DOIs
Publication statusPublished - Jul 10 2020
Externally publishedYes

ASJC Scopus subject areas

  • General

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