@article{f6297af1d533440e891a0dd63948a069,
title = "Structure and gating mechanism of the α7 nicotinic acetylcholine receptor",
abstract = "The α7 nicotinic acetylcholine receptor plays critical roles in the central nervous system and in the cholinergic inflammatory pathway. This ligand-gated ion channel assembles as a homopentamer, is exceptionally permeable to Ca2+, and desensitizes faster than any other Cys-loop receptor. The α7 receptor has served as a prototype for the Cys-loop superfamily yet has proven refractory to structural analysis. We present cryo-EM structures of the human α7 nicotinic receptor in a lipidic environment in resting, activated, and desensitized states, illuminating the principal steps in the gating cycle. The structures also reveal elements that contribute to its function, including a C-terminal latch that is permissive for channel opening, and an anionic ring in the extracellular vestibule that contributes to its high conductance and calcium permeability. Comparisons among the α7 structures provide a foundation for mapping the gating cycle and reveal divergence in gating mechanisms in the Cys-loop receptor superfamily.",
keywords = "Cys-loop receptor, acetylcholine receptor, cryo-EM, ion channel, ligand-gated ion channel, nicotinic receptor, α7",
author = "Noviello, {Colleen M.} and Anant Gharpure and Nuriya Mukhtasimova and Rico Cabuco and Leah Baxter and Dominika Borek and Sine, {Steven M.} and Hibbs, {Ryan E.}",
note = "Funding Information: We thank Richard Walsh and Jinfeng Teng for early contributions to α7 studies. Single-particle cryo-EM grids were screened at the University of Texas Southwestern Medical Center Cryo-Electron Microscopy Facility, which is supported by the CPRIT Core Facility Support Award RP170644 . We thank Harry Scott for cryo-EM data collection at the PNCC under user proposal 50839. A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research . This work was supported by grants from the NIH ( NS120496 , NS077983 , and NS095899 to R.E.H., and NS94124 to S.M.S.) and by the Friends of the Alzheimer{\textquoteright}s Disease Center to R.E.H. Funding Information: We thank Richard Walsh and Jinfeng Teng for early contributions to ?7 studies. Single-particle cryo-EM grids were screened at the University of Texas Southwestern Medical Center Cryo-Electron Microscopy Facility, which is supported by the CPRIT Core Facility Support Award RP170644. We thank Harry Scott for cryo-EM data collection at the PNCC under user proposal 50839. A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. This work was supported by grants from the NIH (NS120496, NS077983, and NS095899 to R.E.H. and NS94124 to S.M.S.) and by the Friends of the Alzheimer's Disease Center to R.E.H. C.M.N. designed experiments, prepared samples, collected and processed cryo-EM data, built and analyzed models, and wrote the manuscript. A.G. performed whole-cell electrophysiology and permeability measurements. N.M. performed single-channel electrophysiology experiments and analysis. R.C. and L.B. performed baculovirus production and mammalian cell culture. D.B. aided in model building. S.M.S. performed binding assays. L.B. helped make figures. R.E.H. C.M.N. and S.M.S. revised the manuscript with input from all authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "15",
doi = "10.1016/j.cell.2021.02.049",
language = "English (US)",
volume = "184",
pages = "2121--2134.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "8",
}