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Type A γ-aminobutyric acid (GABA A ) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system 1 , 2 . Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia 3 , 4 . Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the α1β2/3γ2 GABA A receptors 5 . The β3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in β1–β3 triple knockout neurons 6 . So far, efforts to generate accurate structural models for heteromeric GABA A receptors have been hampered by the use of engineered receptors and the presence of detergents 7 – 9 . Notably, some recent cryo-electron microscopy reconstructions have reported ‘collapsed’ conformations 8 , 9 ; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor 10 , 11 , the large body of structural work on homologous homopentameric receptor variants 12 and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human α1β3γ2L—a major synaptic GABA A receptor isoform—that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator ‘megabody’ and is in a desensitized conformation. Each GABA A receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of α1 subunits. Beyond this level, the intracellular M3–M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABA A receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology. A high-resolution cryo-electron microscopy structure is reported for the full-length human α1β3γ2L GABA A receptor, functionally reconstituted in lipid nanodiscs.

Crystal structures of a chimeric GABA A receptor define new allosteric binding sites for inhibitory and potentiating neurosteroids within the α subunit transmembrane domain. γ-Aminobutyric acid receptors (GABA A Rs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result from receptor dysfunction. A critical component of most native GABA A Rs is the α subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact anxiety, stress and depression, and for therapeutic drugs, such as general anesthetics. Understanding the basis for the modulation of GABA A R function requires high-resolution structures. Here we present the first atomic structures of a GABA A R chimera at 2.8-Å resolution, including those bound with potentiating and inhibitory neurosteroids. These structures define new allosteric binding sites for these modulators that are associated with the α-subunit transmembrane domain. Our findings will enable the exploitation of neurosteroids for therapeutic drug design to regulate GABA A Rs in neurological disorders.

Type-A γ-aminobutyric (GABA A ) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABA A receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA A receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABA A receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABA A receptor modulators. Cryo-electron microscopy structures are reported in which the full-length human α1β3γ2L GABA A receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA, and the benzodiazepines alprazolam and diazepam.

Type-A γ-aminobutyric (GABA ) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABA receptor modulators.

The diversity of nicotinic acetylcholine receptor (nAChR) subtypes was explored by measuring the effects of gene deletion and pharmacological diversity of epibatidine binding sites in mouse brain. All epibatidine binding sites require expression of either the α7, β2, or β4 subunit. In agreement with general belief, the α4β2*-nAChR and α7-nAChR subtypes are major components of the epibatidine binding sites. α4β2*-nAChR sites account for approximately 70% of total high- and low-affinity epibatidine binding sites, while α7-nAChR accounts for 16% of the total sites all of which have lower affinity for epibatidine. The other subtypes are structurally diverse. Although these minor subtypes account for only 14% of total binding in whole brain, they are expressed at relatively high concentrations in specific brain areas indicating unique functional roles.

γ-Aminobutyric acid receptors (GABA Rs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result from receptor dysfunction. A critical component of most native GABA Rs is the α subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact anxiety, stress and depression, and for therapeutic drugs, such as general anesthetics. Understanding the basis for the modulation of GABA R function requires high-resolution structures. Here we present the first atomic structures of a GABA R chimera at 2.8-Å resolution, including those bound with potentiating and inhibitory neurosteroids. These structures define new allosteric binding sites for these modulators that are associated with the α-subunit transmembrane domain. Our findings will enable the exploitation of neurosteroids for therapeutic drug design to regulate GABA Rs in neurological disorders.

In Fig. 5b, d, the arrows showing transmembrane domain rotations were inadvertently pointing clockwise instead of anticlockwise. Similarly, 'anticlockwise' should have been 'clockwise' in the sentence 'This conformational change of the ECD triggers a clockwise rotation of the TMD.' In Extended Data Table 1, the units of the column 'Model resolution' should have been Å instead of Å.sup.2. These errors have been corrected online.

Type A [gamma]-aminobutyric acid (GABA.sub.A) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system.sup.1,2. Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia.sup.3,4. Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the [alpha]1[beta]2/3[gamma]2 GABA.sub.A receptors.sup.5. The [beta]3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in [beta]1-[beta]3 triple knockout neurons.sup.6. So far, efforts to generate accurate structural models for heteromeric GABA.sub.A receptors have been hampered by the use of engineered receptors and the presence of detergents.sup.7-9. Notably, some recent cryo-electron microscopy reconstructions have reported 'collapsed' conformations.sup.8,9; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor.sup.10,11, the large body of structural work on homologous homopentameric receptor variants.sup.12 and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human [alpha]1[beta]3[gamma]2L--a major synaptic GABA.sub.A receptor isoform--that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator 'megabody' and is in a desensitized conformation. Each GABA.sub.A receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of [alpha]1 subunits. Beyond this level, the intracellular M3-M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABA.sub.A receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.

Type-A [gamma]-aminobutyric (GABA.sub.A) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABA.sub.A receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human [alpha]1[beta]3[gamma]2L GABA.sub.A receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA ([gamma]-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABA.sub.A receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABA.sub.A receptor modulators.

Type A [gamma]-aminobutyric acid (GABA.sub.A) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system.sup.1,2. Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia.sup.3,4. Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the [alpha]1[beta]2/3[gamma]2 GABA.sub.A receptors.sup.5. The [beta]3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in [beta]1-[beta]3 triple knockout neurons.sup.6. So far, efforts to generate accurate structural models for heteromeric GABA.sub.A receptors have been hampered by the use of engineered receptors and the presence of detergents.sup.7-9. Notably, some recent cryo-electron microscopy reconstructions have reported 'collapsed' conformations.sup.8,9; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor.sup.10,11, the large body of structural work on homologous homopentameric receptor variants.sup.12 and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human [alpha]1[beta]3[gamma]2L–a major synaptic GABA.sub.A receptor isoform–that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator 'megabody' and is in a desensitized conformation. Each GABA.sub.A receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of [alpha]1 subunits. Beyond this level, the intracellular M3-M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABA.sub.A receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.