Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins

Md Mahfuzur Rahman, Jinfeng Teng, Brady T. Worrell, Colleen M. Noviello, Myeongseon Lee, Arthur Karlin, Michael H.B. Stowell, Ryan E. Hibbs

Research output: Contribution to journalArticle

Abstract

The nicotinic acetylcholine receptor, a pentameric ligand-gated ion channel, converts the free energy of binding of the neurotransmitter acetylcholine into opening of its central pore. Here we present the first high-resolution structure of the receptor type found in muscle-endplate membrane and in the muscle-derived electric tissues of fish. The native receptor was purified from Torpedo electric tissue and functionally reconstituted in lipids optimal for cryo-electron microscopy. The receptor was stabilized in a closed state by the binding of α-bungarotoxin. The structure reveals the binding of a toxin molecule at each of two subunit interfaces in a manner that would block the binding of acetylcholine. It also reveals a closed gate in the ion-conducting pore, formed by hydrophobic amino acid side chains, located ∼60 Å from the toxin binding sites. The structure provides a framework for understanding gating in ligand-gated channels and how mutations in the acetylcholine receptor cause congenital myasthenic syndromes. Rahman et al. report the high-resolution single-particle cryo-EM structure of a native muscle-type nicotinic acetylcholine receptor from the Torpedo electric ray, in complex with α-bungarotoxin from the banded krait. The structure was obtained in a lipidic environment shown to support channel function and reveals a closed, hydrophobic ion channel gate.

Original languageEnglish (US)
Pages (from-to)952-962.e5
JournalNeuron
Volume106
Issue number6
DOIs
StatePublished - Jun 17 2020

Keywords

  • acetylcholine receptor
  • cryo-EM
  • Cys-loop receptor
  • ion channel structure
  • ligand-gated ion channel
  • membrane protein
  • nicotinic receptor
  • Torpedo
  • toxin
  • α-bungarotoxin

ASJC Scopus subject areas

  • Neuroscience(all)

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    Rahman, M. M., Teng, J., Worrell, B. T., Noviello, C. M., Lee, M., Karlin, A., Stowell, M. H. B., & Hibbs, R. E. (2020). Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins. Neuron, 106(6), 952-962.e5. https://doi.org/10.1016/j.neuron.2020.03.012