@article{7697f8f8b3e24e1c9d0325f2d0b3fa06,
title = "Shared structural mechanisms of general anaesthetics and benzodiazepines",
abstract = "Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain1–5. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABAA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABAA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABAA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.",
author = "Kim, {Jeong Joo} and Anant Gharpure and Jinfeng Teng and Yuxuan Zhuang and Howard, {Rebecca J.} and Shaotong Zhu and Noviello, {Colleen M.} and Walsh, {Richard M.} and Erik Lindahl and Hibbs, {Ryan E.}",
note = "Funding Information: Acknowledgements We thank R. Cabuco and L. Baxter for baculovirus production, and all members of the Hibbs laboratory for discussion. Single-particle cryo-EM data were collected at the University of Texas Southwestern Medical Center Cryo-Electron Microscopy Facility, which is supported by the CPRIT Core Facility Support Award RP170644, at the Harvard Cryo-Electron Microscopy Center for Structural Biology, and at the Pacific Northwest Cryo-EM Center at Oregon Health & Science University, which is supported by NIH grant U24GM129547, accessed through EMSL (grid.436923.9) a DOE office of Science User Facility sponsored by the Office of Biological and Environmental Research. Computational resources were provided by the Swedish National Infrastructure for Computing. J.J.K. and S.Z. acknowledge support from the American Heart Association grants 20POST35200127 and 18POST34030412, respectively. This work was supported by Vetenskapsr{\aa}det VR and the Knut and Alice Wallenberg foundation to E.L. and by The Welch Foundation (I-1812) and grants from the NIH (DA037492, DA042072, and NS095899) to R.E.H. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = sep,
day = "10",
doi = "10.1038/s41586-020-2654-5",
language = "English (US)",
volume = "585",
pages = "303--308",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7824",
}