GABA_A Receptor Family: Overview on Structural Characterization

References

• Schofield PR Darlison MG Fujita N et al. Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family . Nature328 ( 6127 ), 221 ( 1987 ).
   PubMed Web of Science ®Google Scholar
• Olsen RW Sieghart W . International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid A receptors: classification on the basis of subunit composition, pharmacology, and function. Update . Pharmacol. Rev.50 ( 2 ), 291 – 313 ( 1998 ).
   PubMed Web of Science ®Google Scholar
• Langosch D Thomas L Betz H . Conserved quaternary structure of ligand-gated ion channels: the postsynaptic glycine receptor is a pentamer . Proc. Natl Acad. Sci.85 ( 19 ), 7394 – 7398 ( 1988 ).
   PubMed Web of Science ®Google Scholar
• Cully DF Vassilatis DK Liu KK et al. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans . Nature371 ( 6499 ), 707 ( 1994 ).
   PubMed Web of Science ®Google Scholar
• Noda M Takahashi H Tanabe T et al. Structural homology of Torpedo californica acetylcholine receptor subunits . Nature302 ( 5908 ), 528 ( 1983 ).
   PubMed Web of Science ®Google Scholar
• Maricq AV Peterson AS Brake AJ Myers RM Julius D . Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel . Science254 ( 5030 ), 432 – 437 ( 1991 ).
   PubMed Web of Science ®Google Scholar
• Davies PA Wang W Hales TG Kirkness EF . A novel class of ligand-gated ion channel is activated by Zn2+ . J. Biol. Chem.278 ( 2 ), 712 – 717 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Ortells MO Lunt GG . Evolutionary history of the ligand-gated ion-channel superfamily of receptors . Trends Neurosci.18 ( 3 ), 121 – 127 ( 1995 ).
   PubMed Web of Science ®Google Scholar
• Jaiteh M Taly A Hénin J . Evolution of pentameric ligand-gated ion channels: pro-loop receptors . PLoS ONE11 ( 3 ), e0151934 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Keramidas A Moorhouse AJ Schofield PR Barry PH . Ligand-gated ion channels: mechanisms underlying ion selectivity . Prog. Biophys. Mol. Biol.86 ( 2004 ), 161 – 204 ( 2010 ).
   Google Scholar
• Imoto K Busch C Sakmann B et al. Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance . Nature335 ( 13 ), 645 – 648 ( 1988 ).
   PubMedGoogle Scholar
• Albuquerque EX Pereira EFR Alkondon M Rogers SW . Mammalian nicotinic acetylcholine receptors: from structure to function . Physiol. Rev.89 ( 1 ), 73 – 120 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Ulens C Spurny R Thompson AJ et al. The prokaryote ligand-gated ion channel ELIC captured in a pore blocker-bound conformation by the Alzheimer's disease drug memantine . Structure22 ( 10 ), 1399 – 1407 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Amundarain MJ Viso JF Zamarreño F Giorgetti A Costabel M . Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods . J. Biomol. Struct. Dyn.4 , 1 – 19 ( 2018 ) ( Epub ahead of print ).
   Google Scholar
• Baumann SW Baur R Sigel E . Forced subunit assembly in α1 β2γ2 GABAA receptors: insight into the absolute arrangement . J. Biol. Chem.277 ( 48 ), 46020 – 46025 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Carter CRJ Kozuska JL Dunn SMJ . Insights into the structure and pharmacology of GABAA receptors . Future Med. Chem.2 ( 5 ), 859 – 75 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Froestl W . An historical perspective on GABAergic drugs . Future Med. Chem.3 ( 2 ), 163 – 175 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Olsen RW . Allosteric ligands and their binding sites define γ-aminobutyric acid (GABA) type A receptor subtypes . In : Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part B.Elsevier, Inc. , 167 – 202 , Amsterdam, The Netherlands ( 2015 ).
   Google Scholar
• Miller PS Smart TG . Binding, activation and modulation of Cys-loop receptors . Trends Pharmacol. Sci.31 ( 4 ), 161 – 174 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Althoff T Hibbs RE Banerjee S Gouaux E . X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors . Nature512 ( 7514 ), 333 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Zhang J Xue F Liu Y Yang H Wang X . The structural mechanism of the Cys-loop receptor desensitization . Mol. Neurobiol.48 ( 1 ), 97 – 108 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Gielen M Thomas P Smart TG . The desensitization gate of inhibitory Cys-loop receptors . Nat. Commun.6 , 1 – 10 ( 2015 ).
   Web of Science ®Google Scholar
• Huang X Chen H Michelsen K Schneider S Shaffer PL . Crystal structure of human glycine receptor-α3 bound to antagonist strychnine . Nature536 ( 7572 ), 277 – 280 ( 2015 ).
   Google Scholar
• Calimet N Simoes M Changeux J-P Karplus M Taly A Cecchini M . A gating mechanism of pentameric ligand-gated ion channels . Proc. Natl Acad. Sci. USA110 ( 42 ), E3987 – E3996 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Dacosta CJB Baenziger JE . Gating of pentameric ligand-gated ion channels: structural insights and ambiguities . Structure21 ( 8 ), 1271 – 1283 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Lape R Colquhoun D Sivilotti LG . On the nature of partial agonism in the nicotinic receptor superfamily . Nature454 ( 7205 ), 722 – 727 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Jatczak-Śliwa M Terejko K Brodzki M et al. Distinct modulation of spontaneous and GABA-evoked gating by flurazepam shapes cross-talk between agonist-free and liganded GABAA receptor activity . Front. Cell. Neurosci.12 , 1 – 18 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Yuan H Low C Moody OA Jenkins A Traynelis SF . Ionotropic GABA and glutamate receptor mutations and human neurologic diseases . Mol. Pharmacol.88 ( 1 ), 203 – 217 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Earnheart JC Schweizer C Crestani F et al. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states . J. Neurosci.27 ( 14 ), 3845 – 3854 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Möhler H . GABAA receptor diversity and pharmacology . Cell Tissue Res.326 ( 2 ), 505 – 516 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Luscher B Fuchs T . GABAergic control of depression-related brain states . Adv. Pharmacol.73 , 97 – 144 ( 2015 ) ( Epub ahead pf print ).
   PubMedGoogle Scholar
• Mukherjee S Das SK Vaidyanathan K Vasudevan DM . Consequences of alcohol consumption on neurotransmitters – an overview . Curr. Neurovasc. Res.5 ( 4 ), 266 – 272 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Woo T-U Whitehead RE Melchitzky DS Lewis DA . A subclass of prefrontal γ-aminobutyric acid axon terminals are selectively altered in schizophrenia . Proc. Natl Acad. Sci.95 ( 9 ), 5341 – 5346 ( 1998 ).
   PubMed Web of Science ®Google Scholar
• Greenfield LJ . Molecular mechanisms of antiseizure drug activity at GABAA receptors . Seizure22 ( 8 ), 589 – 600 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Shangguan Y Xu X Ganbat B et al. CNTNAP4 impacts epilepsy through GABAA receptors regulation: evidence from temporal lobe epilepsy patients and mouse models . Cereb. Cortex.28 ( 10 ), 1 – 14 ( 2017 ).
   Web of Science ®Google Scholar
• Collins AL Ma D Whitehead PL et al. Investigation of autism and GABA receptor subunit genes in multiple ethnic groups . Neurogenetics7 ( 3 ), 167 – 174 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Mesbah-Oskui L Penna A Orser BA Horner RL . Reduced expression of α5GABAA receptors elicits autism-like alterations in EEG patterns and sleep–wake behavior . Neurotoxicol. Teratol.61 , 115 – 122 ( 2017 ) ( Epub ahead of print ).
   PubMed Web of Science ®Google Scholar
• Berman HM Westbrook J Feng Z et al. The Protein Data Bank . Nucleic Acids Res.28 ( 1 ), 235 – 242 ( 2000 ).
   PubMed Web of Science ®Google Scholar
• Berman HM Henrick K Nakamura H . Announcing the worldwide Protein Data Bank . Nat. Struct. Biol.10 ( 12 ), 980 ( 2003 ).
   PubMedGoogle Scholar
• Rose PW Prlić A Altunkaya A et al. The RCSB protein data bank: Integrative view of protein, gene and 3D structural information . Nucleic Acids Res.45 ( 45D1 ), D271 – D281 ( 2017 ).
   PubMedGoogle Scholar
• Miller PS Aricescu AR . Crystal structure of a human GABAA receptor . Nature512 ( 7514 ), 270 – 275 ( 2015 ).
   Web of Science ®Google Scholar
• Zhu S Noviello CM Teng J Walsh RM Kim JJ Hibbs RE . Structure of a human synaptic GABAA receptor . Nature559 ( 7712 ), 1 ( 2018 ).
   Web of Science ®Google Scholar
• Piccoli S Suku E Garonzi M Giorgetti A . Genome-wide membrane protein structure prediction . Curr. Genomics14 ( 5 ), 324 – 9 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Almén MS Nordström KJV Fredriksson R Schiöth HB . Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin . BMC Biol.7 , 50 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Hendrickson WA . Atomic-level analysis of membrane protein structure . Nat. Struct. Mol. Biol.23 ( 6 ), 464 – 467 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Junge F Schneider B Reckel S Schwarz D Dotsch V Bernhard F . Large-scale production of functional membrane proteins . Cell. Mol. Life Sci.65 ( 11 ), 1729 – 1755 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Koehler Leman J Ulmschneider MB Gray JJ . Computational modeling of membrane proteins . Proteins Struct. Funct. Bioinforma.83 ( 1 ), 1 – 24 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Carpenter EP Beis K Cameron AD Iwata S . Overcoming the challenges of membrane protein crystallography . Curr. Opin. Struct. Biol.18 ( 5 ), 581 – 586 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Vijayan RSK Trivedi N Roy SN et al. Modeling the closed and open state conformations of the GABAA ion channel-plausible structural insights for channel gating . J. Chem. Inf. Model.52 ( 11 ), 2958 – 2969 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Higgins MK Lea SM . On the state of crystallography at the dawn of the electron microscopy revolution . Curr. Opin. Struct. Biol.46 , 95 – 101 ( 2017 ) ( Epub ahead of print ).
   PubMed Web of Science ®Google Scholar
• Birch J Axford D Foadi J Meyer A Eckhardt A . The fine art of integral membrane protein crystallisation . Methods147 , 150 - 162 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Basak S Gicheru Y Samanta A et al. Cryo-EM structure of 5-HT3A receptor in its resting conformation . Nat. Commun.9 ( 514 ), 1 – 10 ( 2018 ).
   PubMedGoogle Scholar
• Miller PS Masiulis S Malinauskas T Kotecha A . Heteromeric GABAA receptor structures in positively-modulated active states . bioRxiv ( 2018 ) ( Preprint ).
   Google Scholar
• Phulera S Zhu H Yu J et al. Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2 heterotrimeric GABAA receptor in complex with GABA illuminates mechanism of receptor assembly and agonist binding . Elife7 ( e39383 ), 1 – 21 ( 2018 ).
   Google Scholar
• Mowrey DD Liu Q Bondarenko V et al. Insights into distinct modulation of α7 and α7β2 nicotinic acetylcholine receptors by the volatile anesthetic . J. Biol. Chem.288 ( 50 ), 35793 – 35800 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Morales-Perez CL Noviello CM Hibbs RE . X-ray structure of the human α4β2 nicotinic receptor . Nature538 ( 7625 ), 411 – 415 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Kouvatsos N Giastas P Chroni-Tzartou D Poulopoulou C Tzartos SJ . Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: ligand-bound α2 homopentamer.113 ( 34 ), 9635 – 40 ( 2016 ).
   Google Scholar
• Miyazawa A Fujiyoshi Y Unwin N . Structure and gating mechanism of the acetylcholine receptor pore . Nature423 ( 6943 ), 949 – 955 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Unwin N . Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution . J. Mol. Biol.346 ( 4 ), 967 – 989 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Zuber B Unwin N . Structure and superorganization of acetylcholine receptor-rapsyn complexes . PNAS110 ( 26 ), 10622 – 10627 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Unwin N Fujiyoshi Y . Gating movement of acetylcholine receptor caught by plunge-freezing . J. Mol. Biol.422 ( 5 ), 617 – 634 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Du J Lu W Wu S Cheng Y Gouaux E . Glycine receptor mechanism elucidated by electron cryo-microscopy . Nature526 ( 7572 ), 224 – 229 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Moraga-cid G Sauguet L Huon C et al. Allosteric and hyperekplexic mutant phenotypes investigated on an α1 glycine receptor transmembrane structure . Proc. Natl Acad. Sci. USA112 ( 9 ), 2865 – 2870 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Huang X Chen H Michelsen K Schneider S Shaffer PL . Crystal structure of human glycine receptor-α3 bound to antagonist strychnine . Nature536 ( 7572 ), 277 – 280 ( 2015 ).
   Google Scholar
• Huang X Chen H Shaffer PL . Crystal structures of human GlyR α3 bound to ivermectin . Struct. Des.25 ( 6 ), 1 – 6 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Huang X Shaffer PL Ayube S et al. Crystal structures of human GlyR α3 bound to a novel class of potentiators with efficacy in a mouse model of neuropathic pain . Nat. Struct. Mol. Biol.24 ( 3 ), 108 ( 2017 ).
   PubMedGoogle Scholar
• Hilf RJC Dutzler R . X-ray structure of a prokaryotic pentameric ligand-gated ion channel . Nature452 ( 7185 ), 375 – 379 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Zimmermann I Dutzler R . Ligand activation of the prokaryotic pentameric ligand-gated ion channel ELIC . PLoS Biol.9 ( 6 ), e1001101 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Zimmermann I Marabelli A Bertozzi C Sivilotti LG Dutzler R . Inhibition of the prokaryotic pentameric ligand-gated ion channel ELIC by divalent cations . PLoS Biol.10 ( 11 ), e1001429 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Spurny R Ramerstorfer J Price K et al. Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines . Proc. Natl Acad. Sci. USA109 ( 44 ), E3028 – E3034 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Pan J Chen Q Willenbring D et al. Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine . Nat. Commun.3 , 714 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Gonzalez-Gutierrez G Lukk T Agarwal V Papke D Nair SK Grosman C . Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals . Proc. Natl Acad. Sci. USA109 ( 16 ), 6331 – 6336 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Spurny R Billen B Howard RJ et al. Multisite binding of a general anesthetic to the prokaryotic pentameric Erwinia chrysanthemi ligand-gated ion channel (ELIC) . J. Biol. Chem.288 ( 12 ), 8355 – 8364 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Chen Q Kinde MN Arjunan P et al. Direct pore binding as a mechanism for isoflurane inhibition of the pentameric ligand-gated ion channel ELIC . Sci. Rep.5 ( 6 ), 13833 ( 2015 ).
   PubMedGoogle Scholar
• Bertozzi C Zimmermann I Engeler S Hilf RJC Dutzler R . Signal transduction at the domain interface of prokaryotic pentameric ligand-gated ion channels . PLoS Biol.14 ( 3 ), e1002393 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Nys M Wijckmans E Farinha A et al. Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine . Proc. Natl Acad. Sci.113 ( 43 ), E6696 – E6703 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Chen Q Wells MM Tillman TS et al. Structural basis of alcohol inhibition of the pentameric ligand-gated ion channel ELIC . Structure25 ( 1 ), 180 – 187 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Schmandt N Velisetty P Chalamalasetti SV et al. A chimeric prokaryotic pentameric ligand-gated channel reveals distinct pathways of activation . J. Gen. Physiol.146 ( 4 ), 323 – 340 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Hilf RJC Bertozzi C Zimmermann I Reiter A Trauner D Dutzler R . Structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel . Nat. Struct. Mol. Biol.17 ( 11 ), 1330 – 1336 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Bocquet N Nury H Baaden M et al. X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation . Nature457 ( 7225 ), 111 – 114 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Hilf RJC Dutzler R . Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel . Nature457 ( 7225 ), 115 – 118 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Nury H Poitevin F Van Renterghem C et al. One-microsecond molecular dynamics simulation of channel gating in a nicotinic receptor homologue . Proc. Natl Acad. Sci. USA107 ( 14 ), 6275 – 6280 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Nury H Van Renterghem C Weng Y et al. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel . Nature469 ( 7330 ), 428 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Prevost MS Sauguet L Nury H et al. A locally closed conformation of a bacterial pentameric proton-gated ion channel . Nat. Struct. Mol. Biol.19 ( 6 ), 642 – 649 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Pan J Chen Q Willenbring D et al. Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine . Structure20 ( 9 ), 1463 – 1469 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Sauguet L Howard RJ Malherbe L et al. Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel . Nat. Commun.4 , 1697 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Sauguet L Murail S Van C et al. Structural basis for ion permeation mechanism in pentameric ligand-gated ion channels . 32 ( 5 ), 728 – 741 ( 2013 ).
   Google Scholar
• Mowrey D Chen Q Liang Y Liang J Xu Y Tang P . Signal transduction pathways in the pentameric ligand-gated ion channels . PLoS ONE8 ( 5 ), 1 – 8 ( 2013 ).
   Web of Science ®Google Scholar
• Gonzalez-Gutierrez G Cuello LG Nair SK Grosman C . Gating of the proton-gated ion channel from Gloeobacter violaceus at pH 4 as revealed by x-ray crystallography . Proc. Natl Acad. Sci. USA110 ( 46 ), 18716 – 18721 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Sauguet L Shahsavar A Poitevin F et al. Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation . Proc. Natl Acad. Sci. USA111 ( 3 ), 966 – 971 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Fourati Z Delarue M Sauguet L . Structural characterization of potential modulation sites in the extracellular domain of the prokaryotic pentameric proton-gated ion channel GLIC . Acta Crystallogr. Sect. D71 , 454 – 460 ( 2015 ).
   PubMedGoogle Scholar
• Sauguet L Fourati Z Prangé T Delarue M Colloc'h N . Structural basis for xenon inhibition in a cationic pentameric ligand-gated ion channel . PLoS ONE11 ( 2 ), 1 – 17 ( 2016 ).
   Web of Science ®Google Scholar
• Laurent B Murail S Shahsavar A Sauguet L Delarue M Baaden M . Sites of anesthetic inhibitory action on a cationic ligand-gated ion channel . Struct. Des.24 ( 4 ), 595 – 605 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Basak S Schmandt N Gicheru Y Chakrapani S . Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel . Elife.6 , 1 – 28 pii: ee23886 ( 2017 ).
   Web of Science ®Google Scholar
• Fourati Z Ruza RR Laverty D et al. Barbiturates bind in the GLIC ion channel pore and cause inhibition by stabilizing a closed state . J. Biol. Chem.292 ( 5 ), 1550 – 1558 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Gonzalez-Gutierrez G Wang Y Cymes GD Tajkhorshid E Grosman C . Chasing the open-state structure of pentameric ligand-gated ion channels . J. Gen. Physiol.149 ( 12 ), 1119 – 1138 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Nemecz Á Hu H Fourati Z Van Renterghem C Delarue M Corringer PJ . Full mutational mapping of titratable residues helps to identify proton-sensors involved in the control of channel gating in the Gloeobacter violaceus pentameric ligand-gated ion channel . PLoS Biol.15 ( 12 ), 1 – 22 ( 2017 ).
   Web of Science ®Google Scholar
• Zabara A Chong JTY Martiel I et al. Design of ultra-swollen lipidic mesophases for the crystallization of membrane proteins with large extracellular domains . Nat. Commun.9 , 544 – 544 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Hibbs RE Gouaux E . Principles of activation and permeation in an anion-selective Cys-loop receptor . Nature474 ( 7349 ), 54 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Miller PS Scott S Masiulis S et al. Structural basis for GABA A receptor potentiation by neurosteroids . Nat. Struct. Mol. Biol.24 ( 11 ), 986 – 992 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Laverty D Thomas P Field M et al. Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites . Nat. Struct. Mol. Biol.24 ( 11 ), 977 – 985 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Hassaine G Deluz C Grasso L et al. X-ray structure of the mouse serotonin 5-HT3 receptor . Nature512 ( 7514 ), 276 – 281 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Hu H Nemecz Á Van Renterghem C Fourati Z Sauguet L Corringer P . Crystal structures of a pentameric ion channel gated by alkaline pH show a widely open pore and identify a cavity for modulation . Proc. Natl Acad. Sci.115 ( 17 ), E3959 – E3968 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Liu S Xu L Guan F et al. Cryo-EM structure of the human α5β3 GABAA receptor . Cell Res.28 ( 9 ), 958 – 961 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Smit AB Syed NI Shaap D et al. A glia-derived acetylcholine-binding protein that modulates synaptic transmission . Nature411 ( 6835 ), 261 – 268 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Cromer BA Morton CJ Parker MW . Anxiety over GABAA receptor structure relieved by AChBP . Trends Biochem. Sci.27 ( 6 ), 280 – 287 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Brejc K van Dijk WJ Klaassen RV et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors . Nature411 ( 6835 ), 269 – 276 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Le Novère N Grutter T Changeux J-P . Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites . Proc. Natl Acad. Sci. USA99 ( 5 ), 3210 – 3215 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Smit AB Brejc K Syed NI Sixma TK . Structure and function of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor . Ann. NY Acad. Sci.998 ( 1 ), 81 – 92 ( 2003 ).
   PubMedGoogle Scholar
• Unwin N Miyazawa A Li J Fujiyoshi Y . Activation of the nicotinic acetylcholine receptor involves a switch in conformation of the a subunits . J. Mol. Biol.319 ( 5 ), 1165 – 1176 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Hansen SB Sulzenbacher G Huxford T Marchot P Taylor P Bourne Y . Structures of aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations . EMBO J.24 ( 20 ), 3635 – 3646 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Ulens C Hogg RC Celie PH et al. Structural determinants of selective α-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP . Proc. Natl Acad. Sci.103 ( 10 ), 3615 – 3620 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Hilf RJC Dutzler R . X-ray structure of a prokaryotic pentameric ligand-gated ion channel . Nature452 ( 7185 ), 375 – 379 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Tasneem A Iyer LM Jakobsson E Aravind L . Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels . Genome Biol.6 ( 1 ), R4 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Borghese CM Ruiz CI Lee US et al. Identification of an inhibitory alcohol binding site in GABA . ACS Chem. Neurosci.7 ( 1 ), 100 – 108 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Ii WDJ Howard RJ Trudell JR Harris RA . The TM2 6′ position of GABAA receptors mediates alcohol inhibition . J. Pharmacol. Exp. Ther.340 ( 2 ), 445 – 456 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Bali M Akabas MH . The location of a closed channel gate in the GABAA receptor channel . J. Gen. Physiol.129 ( 2 ), 145 – 159 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Chothia C Lesk AM . The relation between the divergence of sequence and structure in proteins . EMBO J.5 ( 4 ), 823 – 826 ( 1986 ).
   PubMed Web of Science ®Google Scholar
• Russell RB Barton GJ . Structural features can be unconserved in proteins with similar folds: an analysis of side-chain to side-chain contacts secondary structure and accessibility . J. Mol. Biol.244 ( 3 ), 332 – 350 ( 1994 ).
   PubMed Web of Science ®Google Scholar
• Russell RB Saqi MAS Sayle RA Bates PA Sternberg MJE . Recognition of analogous and homologous protein folds: analysis of sequence and structure conservation . J. Mol. Biol.269 ( 3 ), 423 – 439 ( 1997 ).
   PubMed Web of Science ®Google Scholar
• Jayakar SS Zhou X Chiara DC et al. Multiple propofol-binding sites in a γ-aminobutyric acid type a receptor (GABAAR) identified using a photoreactive propofol analog . J. Biol. Chem.289 ( 40 ), 27456 – 27468 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Martí-Renom MA Stuart AC Fiser A Sánchez R Melo F Sali A . Comparative protein structure modeling of genes and genomes . Annu. Rev. Biophys. Biomol. Struct.29 , 291 – 325 ( 2000 ).
   PubMedGoogle Scholar
• Schmidt T Bergner A Schwede T . Modeling three-dimensional protein structures for applications in drug design . Drug Discov. Today.19 ( 00 ), 890 – 897 ( 2013 ).
   PubMedGoogle Scholar
• Almeida JG Preto AJ Koukos PI Bonvin AMJJ Moreira IS . Membrane proteins structures: a review on computational modeling tools . Biochim. Biophys. Acta – Biomembr.1859 ( 10 ), 2021 – 2039 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Bali M Jansen M Akabas MH . GABA-induced intersubunit conformational movement in the GABA A receptor α1M1- β2M3 transmembrane subunit interface: experimental basis for homology modeling of an intravenous anesthetic binding site . J. Neurosci.29 ( 10 ), 3083 – 3092 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Ernst M Brauchart D Boresch S Sieghart W . Comparative modeling of GABAA receptors: limits, insights, future developments . Neuroscience119 ( 4 ), 933 – 943 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Payghan PV Bera I Bhattacharyya D Ghoshal N . Capturing state dependent dynamic events of GABAA-receptors: a microscopic look into the structural and functional insights . J. Biomol. Struct. Dyn.34 ( 8 ), 1818 – 1837 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Trudell JR . Unique assignment of interA-subunit association in GABA α1β3γ2 receptors determined by molecular modeling . Biochim. Biophys. Acta – Biomembr.1565 ( 1 ), 91 – 96 ( 2002 ).
   Web of Science ®Google Scholar
• Bera AK Chatav M Akabas MH . GABAA receptor M2-M3 loop secondary structure and changes in accessibility during channel gating . J. Biol. Chem.277 ( 45 ), 43002 – 43010 ( 2002 ).
   PubMed Web of Science ®Google Scholar
• Ernst M Bruckner S Boresch S Sieghart W . Comparative models of GABA A receptor extracellular and transmembrane domains: important insights in pharmacology . Mol. Pharmacol.68 ( 5 ), 1291 – 1300 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• O'Mara M Cromer B Parker M Chung S-HH . Homology model of the GABAA receptor examined using brownian dynamics . Biophys. J.88 ( 5 ), 3286 – 3299 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• Bergmann R Kongsbak K S⊘rensen PL Sander T Balle T . A unified model of the GABAA receptor comprising agonist and benzodiazepine binding sites . PLoS ONE8 ( 1 ), 1 – 13 ( 2013 ).
   Web of Science ®Google Scholar
• Xie HB Sha Y Wang J Cheng MS . Some insights into the binding mechanism of the GABAA receptor: a combined docking and MM-GBSA study . J. Mol. Model.19 ( 12 ), 5489 – 5500 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Sieghart W Sperk G . Subunit composition, distribution and function of GABAA receptor subtypes . Curr. Top. Med. Chem.2 ( 8 ), 795 – 816 ( 2002 ).
   PubMedGoogle Scholar
• Sigel E Buhr A . The benzodiazepine binding site of GABAA receptors . Trends Pharmacol. Sci.18 ( 4 ), 425 – 429 ( 1997 ).
   PubMedGoogle Scholar
• Berezhnoy D Gibbs TT Farb DH . Docking of 1,4-benzodiazepines in the α1/γ2 GABAA receptor modulator site . Mol. Pharmacol.76 ( 1998 ), 440 – 450 ( 2009 ).
   PubMedGoogle Scholar
• Ci S Ren T Su Z . Investigating the putative binding-mode of GABA and diazepam within GABA A receptor using molecular modeling . Protein J.27 ( 2 ), 71 – 78 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Sancar F Ericksen SS Kucken AM Teissere JA Czajkowski C . Structural determinants for high-affinity zolpidem binding to GABA-A receptors . Mol. Pharmacol.71 ( 1 ), 38 – 46 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Richter L De Graaf C Sieghart W et al. Diazepam-bound GABA A receptor models identify new benzodiazepine binding-site ligands . Nat. Chem. Biol.8 ( 5 ), 455 – 464 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Clayton T Chen JL Ernst M et al. An updated unified pharmacophore model of the benzodiazepine binding site on γ-aminobutyric acida receptors: correlation with comparative models . Curr. Med. Chem.14 ( 26 ), 2755 – 2775 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Mokrab Y Bavro VN Mizuguchi K et al. Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor . J. Mol. Graph. Model.26 ( 4 ), 760 – 774 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Middendorp SJ Puthenkalam R Baur R Ernst M Sigel E . Accelerated discovery of novel benzodiazepine ligands by experiment-guided virtual screening . ACS Chem. Biol.9 ( 8 ), 1854 – 1859 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Simeone X Siebert DCB Bampali K et al. Molecular tools for GABA A receptors: high affinity ligands for β 1-containing subtypes . Nat. Sci. Reports7 ( 5674 ), 1 – 12 ( 2017 ).
   PubMedGoogle Scholar
• Mihalik B Pálvölgyi A Bogár F et al. Loop-F of the α-subunit determines the pharmacologic profile of novel competitive inhibitors of GABA A receptors . Eur. J. Pharmacol.798 , 129 – 136 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Massah AR Gharaghani S Ardeshiri H Nahad L . New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABAA receptor . Med. Chem. Res.25 ( 8 ), 1538 – 1550 ( 2016 ).
   Web of Science ®Google Scholar
• Hénin J Salari R Murlidaran S Brannigan G . A predicted binding site for cholesterol on the GABAA receptor . Biophys. J.106 ( 9 ), 1938 – 1949 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Jayakar SS Zhou X Savechenkov PY et al. Positive and negative allosteric modulation of an α1β3γ2 gamma-aminobutyric acid type A (GABAA) receptor by binding to a site in the transmembrane domain at the γ+-β- interface . J. Biol. Chem.290 ( 38 ), 23432 – 23446 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Jayakar SS Zhou X Chiara DC et al. Multiple propofol-binding sites in a γ-aminobutyric acid type a receptor (GABAAR) identified using a photoreactive propofol analog . J. Biol. Chem.289 ( 40 ), 27456 – 27468 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Chiara DC Dostalova Z Jayakar SS Zhou X Miller KW Cohen JB . Mapping general anesthetic binding site(s) in human α1β3 γ- aminobutyric acid type A receptors with [3 H]TDBzl-etomidate, a photoreactive etomidate analog . Biochemistry51 ( 4 ), 836 – 847 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Westergard T Salari R Martin JV Brannigan G . Interactions of L-3,5,3′-triiodothyronine, allopregnanolone, and ivermectin with the GABAA receptor: evidence for overlapping intersubunit binding modes . PLoS ONE10 ( 9 ), 1 – 18 ( 2015 ).
   Web of Science ®Google Scholar
• Charon S Taly A Rodrigo J Perret P Goeldner M . Binding modes of noncompetitive GABA-channel blockers revisited using engineered affinity-labeling reactions combined with new docking studies . J. Agric. Food Chem.59 ( 7 ), 2803 – 2807 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Puthenkalam R Hieckel M Simeone X et al. Structural studies of GABAA receptor binding sites: which experimental structure tells us what? Front. Mol. Neurosci. 9 ( 44 ), 1 – 20 ( 2016 ).
   PubMedGoogle Scholar
• Michatowski MA Kraszewski S Mozrzymas JW . Binding site opening by loop C shift and chloride ion-pore interaction in the GABAA receptor . Phys. Chem. Chem. Phys.19 ( 21 ), 13664 – 13678 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Rossokhin AV . Side chain flexibility and the pore dimensions in the GABA A receptor . J. Comput. Aided. Mol. Des.30 ( 7 ), 559 – 567 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Rossokhin AV . Homology modeling of the transmembrane domain of the GABA A receptor . Biophysics (Oxford)62 ( 5 ), 708 – 716 ( 2017 ).
   Google Scholar
• Alvarez LD Pecci A . Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor . J. Steroid Biochem. Mol. Biol.182 , 72 – 80 ( 2018 ) ( Epub ahead of print ).
   PubMed Web of Science ®Google Scholar
• Hosie AM Wilkins ME Da Silva HMA Smart TG . Endogenous neurosteroids regulate GABAAreceptors through two discrete transmembrane sites . Nature444 ( 7118 ), 486 – 489 ( 2006 ).
   PubMed Web of Science ®Google Scholar
• Li GD Chiara DC Cohen JB Olsen RW . Neurosteroids allosterically modulate binding of the anesthetic etomidate to γ-aminobutyric acid type A receptors . J. Biol. Chem.284 ( 18 ), 11771 – 11775 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Pettersen EF Goddard TD Huang CC et al. UCSF Chimera – a visualization system for exploratory research and analysis . J. Comput. Chem.25 ( 13 ), 1605 – 1612 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Musgaard M Paramo T Domicevica L Andersen OJ Biggin PC . Insights into channel dysfunction from modeling and molecular dynamics simulations . Neuropharmacology132 , 20 – 30 ( 2018 ).
   PubMed Web of Science ®Google Scholar
• Sandal M Duy TP Cona M et al. GOMoDo: a GPCRs online modeling and docking webserver . PLoS ONE8 ( 9 ), 1 – 7 ( 2013 ).
   Web of Science ®Google Scholar