Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist

Shu Xing Li, Sun Huang, Nina Bren, Kaori Noridomi, Cosma D. Dellisanti, Steven M. Sine, Lin Chen

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Abstract

The α7 acetylcholine receptor (AChR) mediates pre-and postsynaptic neurotransmission in the central nervous system and is a potential therapeutic target in neurodegenerative, neuropsychiatric and inflammatory disorders. We determined the crystal structure of the extracellular domain of a receptor chimera constructed from the human α7 AChR and Lymnaea stagnalis acetylcholine binding protein (AChBP), which shares 64% sequence identity and 71% similarity with native Î ± 7. We also determined the structure with bound epibatidine, a potent AChR agonist. Comparison of the structures revealed molecular rearrangements and interactions that mediate agonist recognition and early steps in signal transduction in α7 AChRs. The structures further revealed a ring of negative charge within the central vestibule, poised to contribute to cation selectivity. Structure-guided mutational studies disclosed distinctive contributions to agonist recognition and signal transduction in α7 AChRs. The structures provide a realistic template for structure-aided drug design and for defining structure-function relationships of α7 AChRs.

Original languageEnglish (US)
Pages (from-to)1253-1259
Number of pages7
JournalNature Neuroscience
Volume14
Issue number10
DOIs
StatePublished - Oct 1 2011

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Li, S. X., Huang, S., Bren, N., Noridomi, K., Dellisanti, C. D., Sine, S. M., & Chen, L. (2011). Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist. Nature Neuroscience, 14(10), 1253-1259. https://doi.org/10.1038/nn.2908