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Title: Structural basis of neurosteroid anesthetic action on GABAA receptors

Authors:
ORCiD logo; ; ; ; ; ORCiD logo;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH)
OSTI Identifier:
1506500
Resource Type:
Journal Article
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Chen, Qiang, Wells, Marta M., Arjunan, Palaniappa, Tillman, Tommy S., Cohen, Aina E., Xu, Yan, and Tang, Pei. Structural basis of neurosteroid anesthetic action on GABAA receptors. United States: N. p., 2018. Web. doi:10.1038/s41467-018-06361-4.
Chen, Qiang, Wells, Marta M., Arjunan, Palaniappa, Tillman, Tommy S., Cohen, Aina E., Xu, Yan, & Tang, Pei. Structural basis of neurosteroid anesthetic action on GABAA receptors. United States. doi:10.1038/s41467-018-06361-4.
Chen, Qiang, Wells, Marta M., Arjunan, Palaniappa, Tillman, Tommy S., Cohen, Aina E., Xu, Yan, and Tang, Pei. Fri . "Structural basis of neurosteroid anesthetic action on GABAA receptors". United States. doi:10.1038/s41467-018-06361-4.
@article{osti_1506500,
title = {Structural basis of neurosteroid anesthetic action on GABAA receptors},
author = {Chen, Qiang and Wells, Marta M. and Arjunan, Palaniappa and Tillman, Tommy S. and Cohen, Aina E. and Xu, Yan and Tang, Pei},
abstractNote = {},
doi = {10.1038/s41467-018-06361-4},
journal = {Nature Communications},
issn = {2041-1723},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {9}
}

Works referenced in this record:

General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA A receptor β3 subunit
journal, February 2003

  • Jurd, Rachel; Arras, Margarete; Lambert, Sachar
  • The FASEB Journal, Vol. 17, Issue 2
  • DOI: 10.1096/fj.02-0611fje

Anesthetic sites and allosteric mechanisms of action on Cys-loop ligand-gated ion channels
journal, January 2011

  • Forman, Stuart A.; Miller, Keith W.
  • Canadian Journal of Anesthesia/Journal canadien d'anesthésie, Vol. 58, Issue 2
  • DOI: 10.1007/s12630-010-9419-9

MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes
journal, July 2004

  • Davis, I. W.; Murray, L. W.; Richardson, J. S.
  • Nucleic Acids Research, Vol. 32, Issue Web Server
  • DOI: 10.1093/nar/gkh398

Cryo-EM structure of 5-HT3A receptor in its resting conformation
journal, February 2018


X-ray structure of a prokaryotic pentameric ligand-gated ion channel
journal, March 2008


Principles of activation and permeation in an anion-selective Cys-loop receptor
journal, May 2011


A neurosteroid potentiation site can be moved among GABA A receptor subunits : Neurosteroid potentiation site and GABA
journal, October 2012


Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ16-alphaxalone and their corresponding 17-carbonitrile analogues
journal, November 2010

  • Bandyopadhyaya, Achintya K.; Manion, Brad D.; Benz, Ann
  • Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 22
  • DOI: 10.1016/j.bmcl.2010.09.008

Identification of channel-lining residues in the M2 membrane-spanning segment of the GABA(A) receptor alpha1 subunit
journal, February 1996


Alphaxalone Binds in Inner Transmembrane β+–α− Interfaces of α1β3γ2 γ-Aminobutyric Acid Type A Receptors
journal, January 2018


Glycine receptor mechanism elucidated by electron cryo-microscopy
journal, September 2015


Mutational Analysis of the Putative High-Affinity Propofol Binding Site in Human β 3 Homomeric GABA A Receptors
journal, July 2015

  • Eaton, Megan M.; Cao, Lily Q.; Chen, Ziwei
  • Molecular Pharmacology, Vol. 88, Issue 4
  • DOI: 10.1124/mol.115.100347

Crystal structure of human glycine receptor-α3 bound to antagonist strychnine
journal, September 2015

  • Huang, Xin; Chen, Hao; Michelsen, Klaus
  • Nature, Vol. 526, Issue 7572
  • DOI: 10.1038/nature14972

An Asymmetric Contribution to γ-Aminobutyric Type A Receptor Function of a Conserved Lysine within TM2–3 of α1, β2, and γ2 Subunits
journal, April 2006

  • Hales, Tim G.; Deeb, Tarek Z.; Tang, Haiyan
  • Journal of Biological Chemistry, Vol. 281, Issue 25
  • DOI: 10.1074/jbc.M603599200

General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal
journal, May 2008

  • Franks, Nicholas P.
  • Nature Reviews Neuroscience, Vol. 9, Issue 5
  • DOI: 10.1038/nrn2372

Conformational Changes Underlying Desensitization of the Pentameric Ligand-Gated Ion Channel ELIC
journal, June 2015


Crystal structure of a human GABAA receptor
journal, June 2014


A Functional Comparison of the Antagonists Bicuculline and Picrotoxin at Recombinant GABA A Receptors
journal, January 1996


Multiple Propofol-binding Sites in a γ-Aminobutyric Acid Type A Receptor (GABA A R) Identified Using a Photoreactive Propofol Analog
journal, August 2014

  • Jayakar, Selwyn S.; Zhou, Xiaojuan; Chiara, David C.
  • Journal of Biological Chemistry, Vol. 289, Issue 40
  • DOI: 10.1074/jbc.M114.581728

Modulation of GABAA receptor activity by alphaxalone
journal, March 1987


De novo GABRA1 mutations in Ohtahara and West syndromes
journal, February 2016

  • Kodera, Hirofumi; Ohba, Chihiro; Kato, Mitsuhiro
  • Epilepsia, Vol. 57, Issue 4
  • DOI: 10.1111/epi.13344

Tryptophan Mutations at Azi-Etomidate Photo-Incorporation Sites on α 1 or β 2 Subunits Enhance GABA A Receptor Gating and Reduce Etomidate Modulation
journal, September 2008

  • Stewart, Deirdre; Desai, Rooma; Cheng, Qi
  • Molecular Pharmacology, Vol. 74, Issue 6
  • DOI: 10.1124/mol.108.050500

Large Influence of Cholesterol on Solute Partitioning into Lipid Membranes
journal, March 2012

  • Wennberg, Christian L.; van der Spoel, David; Hub, Jochen S.
  • Journal of the American Chemical Society, Vol. 134, Issue 11
  • DOI: 10.1021/ja211929h

Conformational Transitions Underlying Pore Opening and Desensitization in Membrane-embedded Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)
journal, September 2012

  • Velisetty, Phanindra; Chalamalasetti, Sreevatsa V.; Chakrapani, Sudha
  • Journal of Biological Chemistry, Vol. 287, Issue 44
  • DOI: 10.1074/jbc.M112.401067

How good are my data and what is the resolution?
journal, June 2013

  • Evans, Philip R.; Murshudov, Garib N.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7
  • DOI: 10.1107/S0907444913000061

GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
journal, September 2015


Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors
journal, March 2005

  • Farrant, Mark; Nusser, Zoltan
  • Nature Reviews Neuroscience, Vol. 6, Issue 3
  • DOI: 10.1038/nrn1625

Common Anesthetic-binding Site for Inhibition of Pentameric Ligand-gated Ion Channels
journal, January 2016


Multiple Non-Equivalent Interfaces Mediate Direct Activation of GABAA Receptors by Propofol
journal, August 2016


Rapid parameterization of small molecules using the force field toolkit
journal, September 2013

  • Mayne, Christopher G.; Saam, Jan; Schulten, Klaus
  • Journal of Computational Chemistry, Vol. 34, Issue 32
  • DOI: 10.1002/jcc.23422

NMR structures of the transmembrane domains of the α4β2 nAChR
journal, May 2012

  • Bondarenko, Vasyl; Mowrey, David; Tillman, Tommy
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1818, Issue 5
  • DOI: 10.1016/j.bbamem.2012.02.008

The desensitization gate of inhibitory Cys-loop receptors
journal, April 2015

  • Gielen, Marc; Thomas, Philip; Smart, Trevor G.
  • Nature Communications, Vol. 6, Issue 1
  • DOI: 10.1038/ncomms7829

Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC
journal, January 2017


XDS
journal, January 2010

  • Kabsch, Wolfgang
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
  • DOI: 10.1107/S0907444909047337

Modulation of GABA A receptor function by neuroactive steroids: evidence for heterogeneity of steroid sensitivity of recombinant GABA A receptor isoforms
journal, September 1998

  • Maitra, Rajatavo; Reynolds, James N.
  • Canadian Journal of Physiology and Pharmacology, Vol. 76, Issue 9
  • DOI: 10.1139/y98-091

Refined Structure of the Nicotinic Acetylcholine Receptor at 4Å Resolution
journal, March 2005


Ensemble-Based Virtual Screening for Cannabinoid-Like Potentiators of the Human Glycine Receptor α1 for the Treatment of Pain
journal, March 2015

  • Wells, Marta M.; Tillman, Tommy S.; Mowrey, David D.
  • Journal of Medicinal Chemistry, Vol. 58, Issue 7
  • DOI: 10.1021/jm501873p

Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation
journal, December 2013

  • Sauguet, L.; Shahsavar, A.; Poitevin, F.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 3
  • DOI: 10.1073/pnas.1314997111

An outline of desensitization in pentameric ligand-gated ion channel receptors
journal, August 2012


Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel
journal, November 2008


Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites
journal, November 2006

  • Hosie, Alastair M.; Wilkins, Megan E.; da Silva, Helena M. A.
  • Nature, Vol. 444, Issue 7118
  • DOI: 10.1038/nature05324

Crystal Structures of Human GlyRα3 Bound to Ivermectin
journal, June 2017


Open-Channel Structures of the Human Glycine Receptor α1 Full-Length Transmembrane Domain
journal, October 2013


Coupling of agonist binding to channel gating in the GABAA receptor
journal, January 2003

  • Kash, Thomas L.; Jenkins, Andrew; Kelley, Jill C.
  • Nature, Vol. 421, Issue 6920
  • DOI: 10.1038/nature01280

Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites
journal, October 2017

  • Laverty, Duncan; Thomas, Philip; Field, Martin
  • Nature Structural & Molecular Biology, Vol. 24, Issue 11
  • DOI: 10.1038/nsmb.3477

X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors
journal, August 2014

  • Althoff, Thorsten; Hibbs, Ryan E.; Banerjee, Surajit
  • Nature, Vol. 512, Issue 7514
  • DOI: 10.1038/nature13669

The interaction of anaesthetic steroids with recombinant glycine and GABA A receptors †
journal, May 2004

  • Weir, C. J.; Ling, A. T. Y.; Belelli, D.
  • British Journal of Anaesthesia, Vol. 92, Issue 5
  • DOI: 10.1093/bja/aeh125

LINCS: A linear constraint solver for molecular simulations
journal, September 1997


Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems
journal, June 1993

  • Darden, Tom; York, Darrin; Pedersen, Lee
  • The Journal of Chemical Physics, Vol. 98, Issue 12
  • DOI: 10.1063/1.464397

Identification of a GABAA Receptor Anesthetic Binding Site at Subunit Interfaces by Photolabeling with an Etomidate Analog
journal, November 2006


Structure of a human synaptic GABAA receptor
journal, June 2018


Site-Directed Spin Labeling Reveals Pentameric Ligand-Gated Ion Channel Gating Motions
journal, November 2013


Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Allosteric and hyperekplexic mutant phenotypes investigated on an α 1 glycine receptor transmembrane structure
journal, February 2015

  • Moraga-Cid, Gustavo; Sauguet, Ludovic; Huon, Christèle
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 9
  • DOI: 10.1073/pnas.1417864112

Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors
journal, September 1997

  • Mihic, S. John; Ye, Qing; Wick, Marilee J.
  • Nature, Vol. 389, Issue 6649
  • DOI: 10.1038/38738

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

NMR structures of the human α7 nAChR transmembrane domain and associated anesthetic binding sites
journal, May 2014

  • Bondarenko, Vasyl; Mowrey, David D.; Tillman, Tommy S.
  • Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1838, Issue 5
  • DOI: 10.1016/j.bbamem.2013.12.018

g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation
journal, March 2010

  • Wolf, Maarten G.; Hoefling, Martin; Aponte-Santamaría, Camilo
  • Journal of Computational Chemistry, Vol. 31, Issue 11
  • DOI: 10.1002/jcc.21507

Mapping General Anesthetic Binding Site(s) in Human α1β3 γ-Aminobutyric Acid Type A Receptors with [ 3 H]TDBzl-Etomidate, a Photoreactive Etomidate Analogue
journal, January 2012

  • Chiara, David C.; Dostalova, Zuzana; Jayakar, Selwyn S.
  • Biochemistry, Vol. 51, Issue 4
  • DOI: 10.1021/bi201772m

Ligand Activation of the Prokaryotic Pentameric Ligand-Gated Ion Channel ELIC
journal, June 2011


GABAA receptors: Subtypes provide diversity of function and pharmacology
journal, January 2009


Structural basis for GABAA receptor potentiation by neurosteroids
journal, October 2017

  • Miller, Paul S.; Scott, Suzanne; Masiulis, Simonas
  • Nature Structural & Molecular Biology, Vol. 24, Issue 11
  • DOI: 10.1038/nsmb.3484

X-ray structure of the human α4β2 nicotinic receptor
journal, October 2016

  • Morales-Perez, Claudio L.; Noviello, Colleen M.; Hibbs, Ryan E.
  • Nature, Vol. 538, Issue 7625
  • DOI: 10.1038/nature19785

X-ray structure of the mouse serotonin 5-HT3 receptor
journal, August 2014

  • Hassaine, Ghérici; Deluz, Cédric; Grasso, Luigino
  • Nature, Vol. 512, Issue 7514
  • DOI: 10.1038/nature13552

Extrasynaptic GABAA Receptors: Their Function in the CNS and Implications for Disease
journal, January 2012


Inhibition of the Prokaryotic Pentameric Ligand-Gated Ion Channel ELIC by Divalent Cations
journal, November 2012


ELIC-α7 Nicotinic Acetylcholine Receptor (α7nAChR) Chimeras Reveal a Prominent Role of the Extracellular-Transmembrane Domain Interface in Allosteric Modulation
journal, April 2014

  • Tillman, Tommy S.; Seyoum, Edom; Mowrey, David D.
  • Journal of Biological Chemistry, Vol. 289, Issue 20
  • DOI: 10.1074/jbc.M113.524611

Conserved site for neurosteroid modulation of GABAA receptors
journal, January 2009


Desensitization Mechanism in Prokaryotic Ligand-gated Ion Channel
journal, April 2012

  • Velisetty, Phanindra; Chakrapani, Sudha
  • Journal of Biological Chemistry, Vol. 287, Issue 22
  • DOI: 10.1074/jbc.M112.348045

Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

VMD: Visual molecular dynamics
journal, February 1996