Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2012 Oct 30;10944:E3028-34. doi: 10.1073/pnas.1208208109.
Show Gene links
Show Anatomy links
Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines.
Spurny R
,
Ramerstorfer J
,
Price K
,
Brams M
,
Ernst M
,
Nury H
,
Verheij M
,
Legrand P
,
Bertrand D
,
Bertrand S
,
Dougherty DA
,
de Esch IJ
,
Corringer PJ
,
Sieghart W
,
Lummis SC
,
Ulens C
.
???displayArticle.abstract???
GABA(A) receptors are pentameric ligand-gated ion channels involved in fast inhibitory neurotransmission and are allosterically modulated by the anxiolytic, anticonvulsant, and sedative-hypnotic benzodiazepines. Here we show that the prokaryotic homolog ELIC also is activated by GABA and is modulated by benzodiazepines with effects comparable to those at GABA(A) receptors. Crystal structures reveal important features of GABA recognition and indicate that benzodiazepines, depending on their concentration, occupy two possible sites in ELIC. An intrasubunit site is adjacent to the GABA-recognition site but faces the channel vestibule. A second intersubunit site partially overlaps with the GABA site and likely corresponds to a low-affinity benzodiazepine-binding site in GABA(A) receptors that mediates inhibitory effects of the benzodiazepine flurazepam. Our study offers a structural view how GABA and benzodiazepines are recognized at a GABA-activated ion channel.
Amin,
Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acidA receptors.
1997, Pubmed,
Xenbase
Amin,
Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acidA receptors.
1997,
Pubmed
,
Xenbase
Amin,
GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital.
1993,
Pubmed
,
Xenbase
Baur,
Covalent modification of GABAA receptor isoforms by a diazepam analogue provides evidence for a novel benzodiazepine binding site that prevents modulation by these drugs.
2008,
Pubmed
,
Xenbase
Berezhnoy,
On the benzodiazepine binding pocket in GABAA receptors.
2004,
Pubmed
,
Xenbase
Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed
Boileau,
Mapping the agonist binding site of the GABAA receptor: evidence for a beta-strand.
1999,
Pubmed
,
Xenbase
Brams,
A structural and mutagenic blueprint for molecular recognition of strychnine and d-tubocurarine by different cys-loop receptors.
2011,
Pubmed
Brams,
Crystal structures of a cysteine-modified mutant in loop D of acetylcholine-binding protein.
2011,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Buhr,
Point mutations of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid(A) receptor affecting modulation of the channel by ligands of the benzodiazepine binding site.
1996,
Pubmed
,
Xenbase
Buhr,
Residues at positions 206 and 209 of the alpha1 subunit of gamma-aminobutyric AcidA receptors influence affinities for benzodiazepine binding site ligands.
1997,
Pubmed
,
Xenbase
Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed
Chevrot,
GABA controls the level of quorum-sensing signal in Agrobacterium tumefaciens.
2006,
Pubmed
Dellisanti,
Structural determinants for alpha-neurotoxin sensitivity in muscle nAChR and their implications for the gating mechanism.
2007,
Pubmed
Dey,
In search of allosteric modulators of a7-nAChR by solvent density guided virtual screening.
2011,
Pubmed
Duncalfe,
The major site of photoaffinity labeling of the gamma-aminobutyric acid type A receptor by [3H]flunitrazepam is histidine 102 of the alpha subunit.
1996,
Pubmed
Dunn,
Mutagenesis of the rat alpha1 subunit of the gamma-aminobutyric acid(A) receptor reveals the importance of residue 101 in determining the allosteric effects of benzodiazepine site ligands.
1999,
Pubmed
,
Xenbase
Ernst,
Comparative modeling of GABA(A) receptors: limits, insights, future developments.
2003,
Pubmed
Goldschen-Ohm,
Three arginines in the GABAA receptor binding pocket have distinct roles in the formation and stability of agonist- versus antagonist-bound complexes.
2011,
Pubmed
Hanson,
Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
2008,
Pubmed
Harrison,
Locating the carboxylate group of GABA in the homomeric rho GABA(A) receptor ligand-binding pocket.
2006,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Hilf,
X-ray structure of a prokaryotic pentameric ligand-gated ion channel.
2008,
Pubmed
Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed
Kucken,
Identification of benzodiazepine binding site residues in the gamma2 subunit of the gamma-aminobutyric acid(A) receptor.
2000,
Pubmed
Lummis,
Two amino acid residues contribute to a cation-π binding interaction in the binding site of an insect GABA receptor.
2011,
Pubmed
,
Xenbase
Lummis,
A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor.
2005,
Pubmed
Lummis,
Binding sites for [(3)H]GABA, [(3)H]flunitrazepam and [(35)S]TBPS in insect CNS.
1986,
Pubmed
Morlock,
Different residues in the GABAA receptor benzodiazepine binding pocket mediate benzodiazepine efficacy and binding.
2011,
Pubmed
,
Xenbase
Padgett,
Unnatural amino acid mutagenesis of the GABA(A) receptor binding site residues reveals a novel cation-pi interaction between GABA and beta 2Tyr97.
2007,
Pubmed
,
Xenbase
Pan,
Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine.
2012,
Pubmed
Ramerstorfer,
The GABAA receptor alpha+beta- interface: a novel target for subtype selective drugs.
2011,
Pubmed
,
Xenbase
Revah,
Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor.
1991,
Pubmed
,
Xenbase
Robinson,
gamma-Aminobutyric acid receptor complex of insect CNS: characterization of a benzodiazepine binding site.
1986,
Pubmed
Sieghart,
Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes.
1995,
Pubmed
Sigel,
A closer look at the high affinity benzodiazepine binding site on GABAA receptors.
2011,
Pubmed
,
Xenbase
Singh,
Antidepressant binding site in a bacterial homologue of neurotransmitter transporters.
2007,
Pubmed
Tan,
Relative positioning of diazepam in the benzodiazepine-binding-pocket of GABA receptors.
2009,
Pubmed
,
Xenbase
Teissére,
A (beta)-strand in the (gamma)2 subunit lines the benzodiazepine binding site of the GABA A receptor: structural rearrangements detected during channel gating.
2001,
Pubmed
,
Xenbase
Wagner,
An arginine involved in GABA binding and unbinding but not gating of the GABA(A) receptor.
2004,
Pubmed
Wagner,
Structure and dynamics of the GABA binding pocket: A narrowing cleft that constricts during activation.
2001,
Pubmed
,
Xenbase
Walters,
Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms.
2000,
Pubmed
,
Xenbase
Westh-Hansen,
Arginine residue 120 of the human GABAA receptor alpha 1, subunit is essential for GABA binding and chloride ion current gating.
1999,
Pubmed
Wieland,
A single histidine in GABAA receptors is essential for benzodiazepine agonist binding.
1992,
Pubmed
Wooltorton,
Pharmacological and physiological characterization of murine homomeric beta3 GABA(A) receptors.
1997,
Pubmed
,
Xenbase
Xiu,
Nicotine binding to brain receptors requires a strong cation-pi interaction.
2009,
Pubmed
,
Xenbase
Zhou,
LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.
2007,
Pubmed
Zimmermann,
Ligand activation of the prokaryotic pentameric ligand-gated ion channel ELIC.
2011,
Pubmed