X-ray structure of the human α4β2 nicotinic receptor

Claudio L. Morales-Perez, Colleen M. Noviello, Ryan E. Hibbs

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and have diverse signalling roles in the central nervous system. The nicotinic receptor has been a model system for cell-surface receptors, and specifically for ligand-gated ion channels, for well over a century. In addition to the receptors' prominent roles in the development of the fields of pharmacology and neurobiology, nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction, epilepsy and for neuromuscular blocking agents used during surgery. The overall architecture of the receptor was described in landmark studies of the nicotinic receptor isolated from the electric organ of Torpedo marmorata. Structures of a soluble ligand-binding domain have provided atomic-scale insights into receptor-ligand interactions, while high-resolution structures of other members of the pentameric receptor superfamily provide touchstones for an emerging allosteric gating mechanism. All available high-resolution structures are of homopentameric receptors. However, the vast majority of pentameric receptors (called Cys-loop receptors in eukaryotes) present physiologically are heteromeric. Here we present the X-ray crystallographic structure of the human α4β2 nicotinic receptor, the most abundant nicotinic subtype in the brain. This structure provides insights into the architectural principles governing ligand recognition, heteromer assembly, ion permeation and desensitization in this prototypical receptor class.

Original languageEnglish (US)
Pages (from-to)411-415
Number of pages5
JournalNature
Volume538
Issue number7625
DOIs
StatePublished - 2016

Fingerprint

Nicotinic Receptors
X-Rays
Ligand-Gated Ion Channels
Ligands
Cysteine Loop Ligand-Gated Ion Channel Receptors
Electric Organ
Neuromuscular Blocking Agents
Torpedo
Neuromuscular Diseases
Neurobiology
Neuromuscular Junction
Cell Surface Receptors
Eukaryota
Synaptic Transmission
Epilepsy
Central Nervous System
Pharmacology
Ions
Brain

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

X-ray structure of the human α4β2 nicotinic receptor. / Morales-Perez, Claudio L.; Noviello, Colleen M.; Hibbs, Ryan E.

In: Nature, Vol. 538, No. 7625, 2016, p. 411-415.

Research output: Contribution to journalArticle

Morales-Perez, CL, Noviello, CM & Hibbs, RE 2016, 'X-ray structure of the human α4β2 nicotinic receptor', Nature, vol. 538, no. 7625, pp. 411-415. https://doi.org/10.1038/nature19785
Morales-Perez, Claudio L. ; Noviello, Colleen M. ; Hibbs, Ryan E. / X-ray structure of the human α4β2 nicotinic receptor. In: Nature. 2016 ; Vol. 538, No. 7625. pp. 411-415.
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