Heteromeric GABAA receptor structures in positively-modulated active states

@article{Miller2018HeteromericGR,
  title={Heteromeric GABAA receptor structures in positively-modulated active states},
  author={Paul S. Miller and Simonas Masiulis and Tomas Malinauskas and A. Kotecha and Shanlin Rao and Sreenivas Chavali and Luigi De Colibus and Els Pardon and Saad Hannan and Suzanne Scott and Zhaoyang Sun and Brandon Frenz and Gianni Klesse and Sai Li and Jonathan M. Diprose and C. Alistair Siebert and Robert Esnouf and Frank DiMaio and Stephen J. Tucker and Trevor G. Smart and Jan Steyaert and M. Madan Babu and Mark S. P. Sansom and Juha T. Huiskonen and A. Radu Aricescu},
  journal={bioRxiv},
  year={2018}
}
Type-A γ-aminobutyric acid (GABAA) receptors are pentameric ligand-gated ion channels (pLGICs), typically consisting of α/β/γ subunit combinations. They are the principal mediators of inhibitory neurotransmission throughout the central nervous system and targets of major clinical drugs, such as benzodiazepines (BZDs) used to treat epilepsy, insomnia, anxiety, panic disorder and muscle spasm. However, the structures of heteromeric receptors and the molecular basis of BZD operation remain unknown… Expand
GABAA receptor signalling mechanisms revealed by structural pharmacology
TLDR
This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABAA receptor modulators. Expand
GABAAreceptor signalling mechanisms revealed by structural pharmacology.
Type-A γ-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among theExpand
Cryo-EM structure of the human α5β3 GABAA receptor
TLDR
The assembly principle and the ligand-gating mechanism of GABAA receptors containing both α and β subunits are elucidated, and the cryo-EM density map reveals that five wellresolved subunits form a cylinder-shaped central ion channel in a pseudo-symmetrical arrangement. Expand
Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer
TLDR
A high-resolution cryo-electron microscopy structure of the full-length human α1β3γ2L GABAA receptor, functionally reconstituted in lipid nanodiscs is reported and illustrates the molecular principles of heteromeric GAB AA receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology. Expand
A structural perspective on GABAA receptor pharmacology.
TLDR
This effort culminated with the high-resolution structural analysis of an intact, full-length human heteropentameric receptor, α1β3γ2, in a lipid bilayer and in complex with small molecule ligands including the commonly used benzodiazepines diazepam and alprazolam (Xanax). Expand
Amino acid substitutions in the human homomeric β3 GABAA receptor that enable activation by GABA
TLDR
It is demonstrated that only two substitutions, Q89R and G152T, in β3 GABAAR are sufficient to reconstitute GABA-mediated activation and suggests that Tyr87 prevents inhibitory effects of GABA. Expand
Shared structural mechanisms of general anesthetics and benzodiazepines
TLDR
Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetic and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazines. Expand
The C loop at the orthosteric binding site is critically involved in GABAA receptor gating
TLDR
First evidence that C loop critically controls GABAAR gating is provided, by analyzing the impact of a β2F200 residue mutation of the C loop on gating properties of α1β2γ2 GABAARs. Expand
Multiple functional neurosteroid binding sites on GABAA receptors
TLDR
Using middle-down mass spectrometry, three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human α1β3 GABAA receptor were identified, indicating both the α1 intrasubunit and β3-α1 intersubunit sites are critical for neurosteroids action. Expand
Mutations at the M2 and M3 Transmembrane Helices of the GABAARs α1 and β2 Subunits Affect Primarily Late Gating Transitions Including Opening/Closing and Desensitization
TLDR
How selected point mutations at the M2 and M3 transmembrane segments affect gating transitions of the α1β2γ2 GABAAR is asked and it is reported that these substitutions profoundly altered openings/closings, having some minor effect on preactivation and agonist binding. Expand
...
1
2
...

References

SHOWING 1-10 OF 157 REFERENCES
Structural basis for GABAA receptor potentiation by neurosteroids
TLDR
Crystal structures of a chimeric GABAAR construct in apo and pregnanolone-bound states are reported, illustrating how peripheral lipid ligands can regulate the desensitization gate of GABAARs, a process of broad relevance to pentameric ligand-gated ion channels. Expand
Crystal structure of a human GABAA receptor
TLDR
The first three-dimensional structure of a GABAAR, the human β3 homopentamer, at 3 Å resolution is presented and reveals architectural elements unique to eukaryotic Cys-loop receptors and shows an unexpected structural role for a conserved N-linked glycan. Expand
Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology
TLDR
The isolation of a cloned cDNA encoding a new GABAA receptor subunit, termed γ2, which shares approximately 40% sequence identity with α-and β-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS. Expand
Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites
TLDR
The first atomic structures of a GABAAR chimera at 2.8-Å resolution are presented, including those bound with potentiating and inhibitory neurosteroids, which will enable the exploitation of neurosteroid for therapeutic drug design to regulate GABAARs in neurological disorders. Expand
Molecular mechanisms of the partial allosteric modulatory effects of bretazenil at gamma-aminobutyric acid type A receptor.
TLDR
Drug-induced modifications of GABA-activated Cl- currents in native GABAA receptors of cortical neurons in primary cultures and in recombinant GAB AA receptors transiently expressed in transformed human embryonic kidney cells (293) after transfection with cDNAs encoding different molecular forms of alpha, beta, and gamma subunits of G ABAA receptors are studied. Expand
A single histidine in GABAA receptors is essential for benzodiazepine agonist binding.
TLDR
It is shown that a portion of the large extracellular domain determines sensitivity toward BZ ligands with sedative as well as anxiolytic activities and a single histidine residue in the alpha 1 variant, replaced by an arginine in alpha 6, as a major determinant for high affinity binding of BZ agonists. Expand
Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
GABAA (γ-aminobutyric acidA) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from theExpand
A novel GABAA receptor pharmacology: drugs interacting with the α+β‐ interface
TLDR
Several benzodiazepine site ligands have been identified that selectively interact with GABAA receptor subtypes containing α2βγ2, α3 βγ2 or α5βγ 2 subunits, which indicates that the different α subunit types present in these receptors convey sufficient structural differences to the benzdiazepine binding site to allow specific interaction with certain benzodiazine siteligands. Expand
Two Tyrosine Residues on the α Subunit Are Crucial for Benzodiazepine Binding and Allosteric Modulation of γ-Aminobutyric Acid A Receptors
TLDR
Structural determinants required for the actions of the BZ diazepam (dzp) on recombinant α1β2γ2 GABAA receptors are investigated and it is suggested that Tyr159 and Tyr209 of the α1 subunit may be components ofThe BZ-binding site on α1 β-aminobutyric acid (GABA) receptors. Expand
Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.
GABA(A) (gamma-aminobutyric acid(A)) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident fromExpand
...
1
2
3
4
5
...