GABA_A receptor family: overview on structural characterization

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1 Schofield PR, Darlison MG, Fujita N et al. Sequence and functional expression of the GABA_A receptor shows a ligand-gated receptor super-family. Nature 328(6127), 221 (1987).
  Medline CASGoogle Scholar
• 2 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).
  MedlineGoogle Scholar
• 3 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).
  Medline CASGoogle Scholar
• 4 Cully DF, Vassilatis DK, Liu KK et al. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371(6499), 707 (1994).
  Medline CASGoogle Scholar
• 5 Noda M, Takahashi H, Tanabe T et al. Structural homology of Torpedo californica acetylcholine receptor subunits. Nature 302(5908), 528 (1983).
  Medline CASGoogle Scholar
• 6 Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D. Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254(5030), 432–437 (1991).
  Medline CASGoogle Scholar
• 7 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).
  Medline CASGoogle Scholar
• 8 Ortells MO, Lunt GG. Evolutionary history of the ligand-gated ion-channel superfamily of receptors. Trends Neurosci. 18(3), 121–127 (1995).
  Medline CASGoogle Scholar
• 9 Jaiteh M, Taly A, Hénin J. Evolution of pentameric ligand-gated ion channels: pro-loop receptors. PLoS ONE 11(3), e0151934 (2016).
  MedlineGoogle Scholar
• 10 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
• 11 Imoto K, Busch C, Sakmann B et al. Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance. Nature 335(13), 645–648 (1988).
  Medline CASGoogle Scholar
• 12 Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol. Rev. 89(1), 73–120 (2009).
  Medline CASGoogle Scholar
• 13 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. Structure 22(10), 1399–1407 (2014).
  Medline CASGoogle Scholar
• 14 Amundarain MJ, Viso JF, Zamarreño F, Giorgetti A, Costabel M. Orthosteric and benzodiazepine cavities of the α₁β₂γ₂ GABA_A receptor: insights from experimentally validated in silico methods. J. Biomol. Struct. Dyn. 4, 1–19 (2018) (Epub ahead of print).
  Google Scholar
• 15 Baumann SW, Baur R, Sigel E. Forced subunit assembly in α₁ β₂γ₂ GABA_A receptors: insight into the absolute arrangement. J. Biol. Chem. 277(48), 46020–46025 (2002).
  Medline CASGoogle Scholar
• 16 Carter CRJ, Kozuska JL, Dunn SMJ. Insights into the structure and pharmacology of GABA_A receptors. Future Med. Chem. 2(5), 859–75 (2010).
  CASGoogle Scholar
• 17 Froestl W. An historical perspective on GABAergic drugs. Future Med. Chem. 3(2), 163–175 (2011).
  CASGoogle Scholar
• 18 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). •• A detailed description of allosteric modulators of GABAARs and their binding sites. It reviews the experimental and computational approaches to identification and characterization of the sites.
  Google Scholar
• 19 Miller PS, Smart TG. Binding, activation and modulation of Cys-loop receptors. Trends Pharmacol. Sci. 31(4), 161–174 (2010).
  Medline CASGoogle Scholar
• 20 Althoff T, Hibbs RE, Banerjee S, Gouaux E. X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 512(7514), 333 (2014).
  Medline CASGoogle Scholar
• 21 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).
  Medline CASGoogle Scholar
• 22 Gielen M, Thomas P, Smart TG. The desensitization gate of inhibitory Cys-loop receptors. Nat. Commun. 6, 1–10 (2015).
  Google Scholar
• 23 Huang X, Chen H, Michelsen K, Schneider S, Shaffer PL. Crystal structure of human glycine receptor-α3 bound to antagonist strychnine. Nature 536(7572), 277–280 (2015).
  Google Scholar
• 24 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. USA 110(42), E3987–E3996 (2013).
  Medline CASGoogle Scholar
• 25 Dacosta CJB, Baenziger JE. Gating of pentameric ligand-gated ion channels: structural insights and ambiguities. Structure 21(8), 1271–1283 (2013).
  Medline CASGoogle Scholar
• 26 Lape R, Colquhoun D, Sivilotti LG. On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454(7205), 722–727 (2008).
  Medline CASGoogle Scholar
• 27 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 GABA_A receptor activity. Front. Cell. Neurosci. 12, 1–18 (2018).
  MedlineGoogle Scholar
• 28 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).
  Medline CASGoogle Scholar
• 29 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).
  Medline CASGoogle Scholar
• 30 Möhler H. GABA_A receptor diversity and pharmacology. Cell Tissue Res. 326(2), 505–516 (2006).
  Medline CASGoogle Scholar
• 31 Luscher B, Fuchs T. GABAergic control of depression-related brain states. Adv. Pharmacol. 73, 97–144 (2015) (Epub ahead pf print).
  Medline CASGoogle Scholar
• 32 Mukherjee S, Das SK, Vaidyanathan K, Vasudevan DM. Consequences of alcohol consumption on neurotransmitters – an overview. Curr. Neurovasc. Res. 5(4), 266–272 (2008).
  Medline CASGoogle Scholar
• 33 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).
  Medline CASGoogle Scholar
• 34 Greenfield LJ. Molecular mechanisms of antiseizure drug activity at GABA_A receptors. Seizure 22(8), 589–600 (2013).
  MedlineGoogle Scholar
• 35 Shangguan Y, Xu X, Ganbat B et al. CNTNAP4 impacts epilepsy through GABA_A receptors regulation: evidence from temporal lobe epilepsy patients and mouse models. Cereb. Cortex. 28(10), 1–14 (2017).
  Google Scholar
• 36 Collins AL, Ma D, Whitehead PL et al. Investigation of autism and GABA receptor subunit genes in multiple ethnic groups. Neurogenetics 7(3), 167–174 (2006).
  Medline CASGoogle Scholar
• 37 Mesbah-Oskui L, Penna A, Orser BA, Horner RL. Reduced expression of α₅GABA_A receptors elicits autism-like alterations in EEG patterns and sleep–wake behavior. Neurotoxicol. Teratol. 61, 115–122 (2017) (Epub ahead of print).
  Medline CASGoogle Scholar
• 38 Berman HM, Westbrook J, Feng Z et al. The Protein Data Bank. Nucleic Acids Res. 28(1), 235–242 (2000).
  Medline CASGoogle Scholar
• 39 Berman HM, Henrick K, Nakamura H. Announcing the worldwide Protein Data Bank. Nat. Struct. Biol. 10(12), 980 (2003).
  Medline CASGoogle Scholar
• 40 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).
  Medline CASGoogle Scholar
• 41 Miller PS, Aricescu AR. Crystal structure of a human GABA_A receptor. Nature 512(7514), 270–275 (2015). • Introduces the first crystallographic structure of a GABAAR, the human β3 homopentamer. It was captured in a desensitized state with agonist molecules bound.
  Google Scholar
• 42 Zhu S, Noviello CM, Teng J, Walsh RM, Kim JJ, Hibbs RE. Structure of a human synaptic GABAA receptor. Nature 559(7712), 1 (2018). • Presents the new structure of a GABAA receptor obtained through cryo-electron microscopy. It belongs to the most common isoform in adult humans.
  Google Scholar
• 43 Piccoli S, Suku E, Garonzi M, Giorgetti A. Genome-wide membrane protein structure prediction. Curr. Genomics 14(5), 324–9 (2013).
  Medline CASGoogle Scholar
• 44 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).
  MedlineGoogle Scholar
• 45 Hendrickson WA. Atomic-level analysis of membrane protein structure. Nat. Struct. Mol. Biol. 23(6), 464–467 (2016).
  Medline CASGoogle Scholar
• 46 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).
  Medline CASGoogle Scholar
• 47 Koehler Leman J, Ulmschneider MB, Gray JJ. Computational modeling of membrane proteins. Proteins Struct. Funct. Bioinforma. 83(1), 1–24 (2015).
  Medline CASGoogle Scholar
• 48 Carpenter EP, Beis K, Cameron AD, Iwata S. Overcoming the challenges of membrane protein crystallography. Curr. Opin. Struct. Biol. 18(5), 581–586 (2008).
  Medline CASGoogle Scholar
• 49 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).
  Medline CASGoogle Scholar
• 50 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). •• Focuses on the recent advances in high-resolution electron cryo-microscopy. It offers a thorough comparison between this technique and x-ray crystallography, in addition to prospects on the different structure determination methods.
  Medline CASGoogle Scholar
• 51 Birch J, Axford D, Foadi J, Meyer A, Eckhardt A. The fine art of integral membrane protein crystallisation. Methods 147, 150-162 (2018).
  Medline CASGoogle Scholar
• 52 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).
  Medline CASGoogle Scholar
• 53 Miller PS, Masiulis S, Malinauskas T, Kotecha A. Heteromeric GABA_A receptor structures in positively-modulated active states. bioRxiv(2018) (Preprint).
  Google Scholar
• 54 Phulera S, Zhu H, Yu J et al. Cryo-EM structure of the benzodiazepine-sensitive α₁β₁γ₂ heterotrimeric GABA_A receptor in complex with GABA illuminates mechanism of receptor assembly and agonist binding. Elife 7(e39383), 1–21 (2018).
  Google Scholar
• 55 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).
  Medline CASGoogle Scholar
• 56 Morales-Perez CL, Noviello CM, Hibbs RE. X-ray structure of the human α₄β₂ nicotinic receptor. Nature 538(7625), 411–415 (2016).
  Medline CASGoogle Scholar
• 57 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
• 58 Miyazawa A, Fujiyoshi Y, Unwin N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423(6943), 949–955 (2003).
  Medline CASGoogle Scholar
• 59 Unwin N. Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J. Mol. Biol. 346(4), 967–989 (2005).
  Medline CASGoogle Scholar
• 60 Zuber B, Unwin N. Structure and superorganization of acetylcholine receptor-rapsyn complexes. PNAS 110(26), 10622–10627 (2013).
  Medline CASGoogle Scholar
• 61 Unwin N, Fujiyoshi Y. Gating movement of acetylcholine receptor caught by plunge-freezing. J. Mol. Biol. 422(5), 617–634 (2012).
  Medline CASGoogle Scholar
• 62 Du J, Lu W, Wu S, Cheng Y, Gouaux E. Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature 526(7572), 224–229 (2015).
  Medline CASGoogle Scholar
• 63 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. USA 112(9), 2865–2870 (2015).
  Medline CASGoogle Scholar
• 64 Huang X, Chen H, Michelsen K, Schneider S, Shaffer PL. Crystal structure of human glycine receptor-α3 bound to antagonist strychnine. Nature 536(7572), 277–280 (2015).
  Google Scholar
• 65 Huang X, Chen H, Shaffer PL. Crystal structures of human GlyR α₃ bound to ivermectin. Struct. Des. 25(6), 1–6 (2017).
  MedlineGoogle Scholar
• 66 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).
  MedlineGoogle Scholar
• 67 Hilf RJC, Dutzler R. X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452(7185), 375–379 (2008).
  Medline CASGoogle Scholar
• 68 Zimmermann I, Dutzler R. Ligand activation of the prokaryotic pentameric ligand-gated ion channel ELIC. PLoS Biol. 9(6), e1001101 (2011).
  Medline CASGoogle Scholar
• 69 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).
  Medline CASGoogle Scholar
• 70 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. USA 109(44), E3028–E3034 (2012).
  Medline CASGoogle Scholar
• 71 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).
  MedlineGoogle Scholar
• 72 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. USA 109(16), 6331–6336 (2012).
  Medline CASGoogle Scholar
• 73 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).
  Medline CASGoogle Scholar
• 74 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).
  MedlineGoogle Scholar
• 75 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).
  MedlineGoogle Scholar
• 76 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).
  Medline CASGoogle Scholar
• 77 Chen Q, Wells MM, Tillman TS et al. Structural basis of alcohol inhibition of the pentameric ligand-gated ion channel ELIC. Structure 25(1), 180–187 (2017).
  Medline CASGoogle Scholar
• 78 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).
  Medline CASGoogle Scholar
• 79 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).
  Medline CASGoogle Scholar
• 80 Bocquet N, Nury H, Baaden M et al. X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457(7225), 111–114 (2009).
  Medline CASGoogle Scholar
• 81 Hilf RJC, Dutzler R. Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457(7225), 115–118 (2009).
  Medline CASGoogle Scholar
• 82 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. USA 107(14), 6275–6280 (2010).
  Medline CASGoogle Scholar
• 83 Nury H, Van Renterghem C, Weng Y et al. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469(7330), 428 (2011).
  Medline CASGoogle Scholar
• 84 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).
  Medline CASGoogle Scholar
• 85 Pan J, Chen Q, Willenbring D et al. Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine. Structure 20(9), 1463–1469 (2012).
  Medline CASGoogle Scholar
• 86 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).
  MedlineGoogle Scholar
• 87 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
• 88 Mowrey D, Chen Q, Liang Y, Liang J, Xu Y, Tang P. Signal transduction pathways in the pentameric ligand-gated ion channels. PLoS ONE 8(5), 1–8 (2013).
  Google Scholar
• 89 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. USA 110(46), 18716–18721 (2013).
  Medline CASGoogle Scholar
• 90 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. USA 111(3), 966–971 (2014).
  Medline CASGoogle Scholar
• 91 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. D 71, 454–460 (2015).
  Medline CASGoogle Scholar
• 92 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 ONE 11(2), 1–17 (2016).
  Google Scholar
• 93 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).
  Medline CASGoogle Scholar
• 94 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).
  Google Scholar
• 95 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).
  Medline CASGoogle Scholar
• 96 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).
  Medline CASGoogle Scholar
• 97 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).
  Google Scholar
• 98 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).
  MedlineGoogle Scholar
• 99 Hibbs RE, Gouaux E. Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474(7349), 54 (2011).
  Medline CASGoogle Scholar
• 100 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).
  Medline CASGoogle Scholar
• 101 Laverty D, Thomas P, Field M et al. Crystal structures of a GABA_A-receptor chimera reveal new endogenous neurosteroid-binding sites. Nat. Struct. Mol. Biol. 24(11), 977–985 (2017).
  Medline CASGoogle Scholar
• 102 Hassaine G, Deluz C, Grasso L et al. X-ray structure of the mouse serotonin 5-HT3 receptor. Nature 512(7514), 276–281 (2014).
  Medline CASGoogle Scholar
• 103 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).
  MedlineGoogle Scholar
• 104 Liu S, Xu L, Guan F et al. Cryo-EM structure of the human α5β3 GABA_A receptor. Cell Res. 28(9), 958–961 (2018).
  MedlineGoogle Scholar
• 105 Smit AB, Syed NI, Shaap D et al. A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature 411(6835), 261–268 (2001).
  Medline CASGoogle Scholar
• 106 Cromer BA, Morton CJ, Parker MW. Anxiety over GABA_A receptor structure relieved by AChBP. Trends Biochem. Sci. 27(6), 280–287 (2002).
  Medline CASGoogle Scholar
• 107 Brejc K, van Dijk WJ, Klaassen RV et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411(6835), 269–276 (2001).
  Medline CASGoogle Scholar
• 108 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. USA 99(5), 3210–3215 (2002).
  Medline CASGoogle Scholar
• 109 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).
  Medline CASGoogle Scholar
• 110 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).
  Medline CASGoogle Scholar
• 111 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).
  Medline CASGoogle Scholar
• 112 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).
  Medline CASGoogle Scholar
• 113 Hilf RJC, Dutzler R. X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452(7185), 375–379 (2008).
  Medline CASGoogle Scholar
• 114 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).
  MedlineGoogle Scholar
• 115 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).
  Medline CASGoogle Scholar
• 116 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).
  MedlineGoogle Scholar
• 117 Bali M, Akabas MH. The location of a closed channel gate in the GABA_A receptor channel. J. Gen. Physiol. 129(2), 145–159 (2007).
  Medline CASGoogle Scholar
• 118 Chothia C, Lesk AM. The relation between the divergence of sequence and structure in proteins. EMBO J. 5(4), 823–826 (1986).
  Medline CASGoogle Scholar
• 119 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).
  Medline CASGoogle Scholar
• 120 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).
  Medline CASGoogle Scholar
• 121 Jayakar SS, Zhou X, Chiara DC et al. Multiple propofol-binding sites in a γ-aminobutyric acid type a receptor (GABA_AR) identified using a photoreactive propofol analog. J. Biol. Chem. 289(40), 27456–27468 (2014).
  Medline CASGoogle Scholar
• 122 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).
  Medline CASGoogle Scholar
• 123 Schmidt T, Bergner A, Schwede T. Modeling three-dimensional protein structures for applications in drug design. Drug Discov. Today. 19(00), 890–897 (2013).
  MedlineGoogle Scholar
• 124 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). •• Updated review on in silico techniques available for determination of the 3D structure of membrane proteins and characterization of binding interfaces. Relevant case studies are provided.
  Medline CASGoogle Scholar
• 125 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).
  Medline CASGoogle Scholar
• 126 Ernst M, Brauchart D, Boresch S, Sieghart W. Comparative modeling of GABA_A receptors: limits, insights, future developments. Neuroscience 119(4), 933–943 (2003).
  Medline CASGoogle Scholar
• 127 Payghan PV, Bera I, Bhattacharyya D, Ghoshal N. Capturing state dependent dynamic events of GABA_A-receptors: a microscopic look into the structural and functional insights. J. Biomol. Struct. Dyn. 34(8), 1818–1837 (2016).
  Medline CASGoogle Scholar
• 128 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).
  CASGoogle Scholar
• 129 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).
  Medline CASGoogle Scholar
• 130 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).
  Medline CASGoogle Scholar
• 131 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).
  MedlineGoogle Scholar
• 132 Bergmann R, Kongsbak K, Sørensen PL, Sander T, Balle T. A unified model of the GABA_A receptor comprising agonist and benzodiazepine binding sites. PLoS ONE 8(1), 1–13 (2013).
  Google Scholar
• 133 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).
  Medline CASGoogle Scholar
• 134 Sieghart W, Sperk G. Subunit composition, distribution and function of GABA_A receptor subtypes. Curr. Top. Med. Chem. 2(8), 795–816 (2002).
  Medline CASGoogle Scholar
• 135 Sigel E, Buhr A. The benzodiazepine binding site of GABAA receptors. Trends Pharmacol. Sci. 18(4), 425–429 (1997).
  Medline CASGoogle Scholar
• 136 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).
  Medline CASGoogle Scholar
• 137 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).
  Medline CASGoogle Scholar
• 138 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).
  MedlineGoogle Scholar
• 139 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).
  Medline CASGoogle Scholar
• 140 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).
  Medline CASGoogle Scholar
• 141 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).
  Medline CASGoogle Scholar
• 142 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).
  Medline CASGoogle Scholar
• 143 Simeone X, Siebert DCB, Bampali K et al. Molecular tools for GABA A receptors: high affinity ligands for β 1-containing subtypes. Nat. Sci. Reports 7(5674), 1–12 (2017).
  MedlineGoogle Scholar
• 144 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).
  Medline CASGoogle Scholar
• 145 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).
  CASGoogle Scholar
• 146 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).
  Medline CASGoogle Scholar
• 147 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).
  Medline CASGoogle Scholar
• 148 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).
  Medline CASGoogle Scholar
• 149 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. Biochemistry 51(4), 836–847 (2012).
  Medline CASGoogle Scholar
• 150 Westergard T, Salari R, Martin JV, Brannigan G. Interactions of L-3,5,3′-triiodothyronine, allopregnanolone, and ivermectin with the GABA_A receptor: evidence for overlapping intersubunit binding modes. PLoS ONE 10(9), 1–18 (2015).
  Google Scholar
• 151 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).
  Medline CASGoogle Scholar
• 152 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). • The newest and most comprehensive approach to homology modeling of GABAA receptors and their interaction with novel ligands.
  MedlineGoogle Scholar
• 153 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).
  MedlineGoogle Scholar
• 154 Rossokhin AV. Side chain flexibility and the pore dimensions in the GABA A receptor. J. Comput. Aided. Mol. Des. 30(7), 559–567 (2016).
  Medline CASGoogle Scholar
• 155 Rossokhin AV. Homology modeling of the transmembrane domain of the GABA A receptor. Biophysics (Oxford) 62(5), 708–716 (2017).
  CASGoogle Scholar
• 156 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).
  Medline CASGoogle Scholar
• 157 Hosie AM, Wilkins ME, Da Silva HMA, Smart TG. Endogenous neurosteroids regulate GABAAreceptors through two discrete transmembrane sites. Nature 444(7118), 486–489 (2006).
  Medline CASGoogle Scholar
• 158 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).
  Medline CASGoogle Scholar
• 159 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).
  Medline CASGoogle Scholar
• 160 Musgaard M, Paramo T, Domicevica L, Andersen OJ, Biggin PC. Insights into channel dysfunction from modeling and molecular dynamics simulations. Neuropharmacology 132, 20–30 (2018).
  Medline CASGoogle Scholar
• 161 Sandal M, Duy TP, Cona M et al. GOMoDo: a GPCRs online modeling and docking webserver. PLoS ONE 8(9), 1–7 (2013).
  Google Scholar