Structural Requirements for Eszopiclone and Zolpidem Binding to the γ-Aminobutyric Acid Type-A (GABA<sub>A</sub>) Receptor Are Different

Hanson, Susan M.; Morlock, Elaine V.; Satyshur, Kenneth A.; Czajkowski, Cynthia

doi:10.1021/jm800889m

Cited by 183 publications

(104 citation statements)

References 47 publications

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“…The present study focuses on the orientation of classic BZDs in the binding pocket, and it is unclear whether non-BZD ligands orient similarly; however, mutagenesis and docking studies of the non-BZD ligands zolpidem and eszopiclone indicate that interactions with ␣ 1 His101, ␣ 1 Ser204, and ␥ 2 Arg194 contribute to orienting these ligands in the binding pocket (Hanson et al, 2008).…”

Section: Discussionmentioning

confidence: 95%

Docking of 1,4-Benzodiazepines in the α₁/γ₂GABA_AReceptor Modulator Site

Berezhnoy

Gibbs²,

Farb³

2009

Mol Pharmacol

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Positive allosteric modulation of the GABA A receptor (GABA A R) via the benzodiazepine recognition site is the mechanism whereby diverse chemical classes of therapeutic agents act to reduce anxiety, induce and maintain sleep, reduce seizures, and induce conscious sedation. The binding of such therapeutic agents to this allosteric modulatory site increases the affinity of GABA for the agonist recognition site. A major unanswered question, however, relates to how positive allosteric modulators dock in the 1,4-benzodiazepine (BZD) recognition site. In the present study, the X-ray structure of an acetylcholine binding protein from the snail Lymnea stagnalis and the results from site-directed affinity-labeling studies were used as the basis for modeling of the BZD binding pocket at the ␣ 1 /␥ 2 subunit interface. A tethered BZD was introduced into the binding pocket, and molecular simulations were carried out to yield a set of candidate orientations of the BZD ligand in the binding pocket. Candidate orientations were refined based on known structureactivity and stereospecificity characteristics of BZDs and the impact of the ␣ 1 H101R mutation. Results favor a model in which the BZD molecule is oriented such that the C5-phenyl substituent extends approximately parallel to the plane of the membrane rather than parallel to the ion channel. Application of this computational modeling strategy, which integrates sitedirected affinity labeling with structure-activity knowledge to create a molecular model of the docking of active ligands in the binding pocket, may provide a basis for the design of more selective GABA A R modulators with enhanced therapeutic potential.

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Section: Discussionmentioning

confidence: 95%

Docking of 1,4-Benzodiazepines in the α₁/γ₂GABA_AReceptor Modulator Site

Berezhnoy

Gibbs²,

Farb³

2009

Mol Pharmacol

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“…Mutation of the homologous W55 residue in the GABA A -R ␥2-subunit, F77C, abolished binding by (28). In the GABA A -R ␣1-subunit, it was shown that for the homologous Trp-55 subtle changes were caused by unnatural amino acid mutations (29).…”

Section: Discussionmentioning

confidence: 99%

Crystal Structures of a Cysteine-modified Mutant in Loop D of Acetylcholine-binding Protein

Brams

Gay

Saez

et al. 2011

Journal of Biological Chemistry

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Cys-loop receptors (CLRs) 2 belong to a class of ligandgated ion channels that are involved in fast synaptic transmission in the central nervous system and the neuromuscular junction. This transmission can either be excitatory or inhibitory depending on the charge of ions that pass through the ion conduction pathway of the channel. Excitatory transmission is mediated by nicotinic acetylcholine receptors (nAChR) and 5-HT 3 serotonin receptors, which selectively pass cations. On the other hand, inhibitory transmission is mediated by glycine receptors (GlyR) and ␥-aminobutyric acid (GABA A and GABA C ) receptors, which selectively conduct anions. In both types of receptors, the ion conduction pathway lies along the central axis formed by five channel subunits, which can either be identical for homomeric CLRs or non-identical for heteromeric CLRs. Opening and closing of the ion conduction pathway is controlled by a gate that is allosterically coupled to the extracellular ligand-binding domain (for a recent review see Ref. 1).Detailed structural data are still lacking for an intact eukaryotic CLR, but structural information has been obtained from 4 Å resolution electron microscopic images of the Torpedo nAChR (2) and higher resolution x-ray crystal structures of AChBP, a molluscan homolog of the extracellular domain of nAChRs (3, 4), the monomeric ␣1 nAChR subunit (5), and two prokaryotic homologs ELIC (6) and GLIC (7,8), which presumably represent the closed and open state of a CLR. Despite their different pharmacological properties, these CLRs share a common architectural arrangement of aromatic residues in their ligand-binding site. The ligand-binding site for CLRs is found at the interface between two subunits and ligands interact with amino acids from both the principal face (containing loops A, B, and C) and complementary face (containing loops D, E, and F). We have focused our attention on an aromatic residue that lies on the complementary face of the binding pocket and is highly conserved among eukaryotic and prokaryotic CLRs.Recently, we found that the tryptophan residue at position 55 of the rat ␣7 nAChR (Trp-55) was the site where synthetic * This research was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health, NIEHS (to E. A. G., J. C. S., and J. L. Y.), by G.0257.08), and the Belgian Federal Science Policy Office, Interuniversity Attraction Poles program (P6/31) (to J. T.), EU FP7 2020288 NeuroCypres (to C. U., A. B. S., and R. C. vd. S.), and KULeuven Onderzoekstoelage OT/08/048 (to S. V. S. and C. U.). □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1. The atomic coordinates and structure factors (codes 2XZ6 and 2XZ5)

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“…In the case of the predominant heteromeric receptors where the binding interfaces will differ, such ligands may possibly serve as positive or negative allosteric modulators at sites distinct from those occupied by agonist and competitive antagonist (36). Such appears to be the case for the benzodiazepines (36,37) and other sedative agents (38) that act in this manner with the GABA receptor (39,40). Accordingly, new dimensions for achieving pharmacologic selectivity for particular nAChR subtypes may result with the cooperative nAChR ligands possessing electron-rich substituted 2-aminopyrimidines.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for cooperative interactions of substituted 2-aminopyrimidines with the acetylcholine binding protein

Kaczanowska

Harel

Radić

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The nicotinic acetylcholine receptor (nAChR) and the acetylcholine binding protein (AChBP) are pentameric oligomers in which binding sites for nicotinic agonists and competitive antagonists are found at selected subunit interfaces. The nAChR spontaneously exists in multiple conformations associated with its activation and desensitization steps, and conformations are selectively stabilized by binding of agonists and antagonists. In the nAChR, agonist binding and the associated conformational changes accompanying activation and desensitization are cooperative. AChBP, which lacks the transmembrane spanning and cytoplasmic domains, serves as a homology model of the extracellular domain of the nAChRs. We identified unique cooperative binding behavior of a number of 4,6-disubstituted 2-aminopyrimidines to Lymnaea AChBP, with different molecular variants exhibiting positive, n H > 1.0, and negative cooperativity, n H < 1.0. Therefore, for a distinctive set of ligands, the extracellular domain of a nAChR surrogate suffices to accommodate cooperative interactions. X-ray crystal structures of AChBP complexes with examples of each allowed the identification of structural features in the ligands that confer differences in cooperative behavior. Both sets of molecules bind at the agonist-antagonist site, as expected from their competition with epibatidine. An analysis of AChBP quaternary structure shows that cooperative ligand binding is associated with a blooming or flare conformation, a structural change not observed with the classical, noncooperative, nicotinic ligands. Positively and negatively cooperative ligands exhibited unique features in the detailed binding determinants and poses of the complexes.allostery | crystallography | nicotinic receptor

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Structural Requirements for Eszopiclone and Zolpidem Binding to the γ-Aminobutyric Acid Type-A (GABA_A) Receptor Are Different

Cited by 183 publications

References 47 publications

Docking of 1,4-Benzodiazepines in the α₁/γ₂GABA_AReceptor Modulator Site

Docking of 1,4-Benzodiazepines in the α₁/γ₂GABA_AReceptor Modulator Site

Crystal Structures of a Cysteine-modified Mutant in Loop D of Acetylcholine-binding Protein

Structural basis for cooperative interactions of substituted 2-aminopyrimidines with the acetylcholine binding protein

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Structural Requirements for Eszopiclone and Zolpidem Binding to the γ-Aminobutyric Acid Type-A (GABAA) Receptor Are Different

Cited by 183 publications

References 47 publications

Docking of 1,4-Benzodiazepines in the α1/γ2GABAAReceptor Modulator Site

Docking of 1,4-Benzodiazepines in the α1/γ2GABAAReceptor Modulator Site

Crystal Structures of a Cysteine-modified Mutant in Loop D of Acetylcholine-binding Protein

Structural basis for cooperative interactions of substituted 2-aminopyrimidines with the acetylcholine binding protein

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Structural Requirements for Eszopiclone and Zolpidem Binding to the γ-Aminobutyric Acid Type-A (GABA_A) Receptor Are Different

Docking of 1,4-Benzodiazepines in the α₁/γ₂GABA_AReceptor Modulator Site

Docking of 1,4-Benzodiazepines in the α₁/γ₂GABA_AReceptor Modulator Site