A Cation-π Binding Interaction with a Tyrosine in the Binding Site of the GABAC Receptor

Lummis, Sarah C. R.; Beene, Darren L.; Harrison, N.; Lester, Henry A.; Dougherty, Dennis A.

doi:10.1016/j.chembiol.2005.06.012

Cited by 129 publications

(142 citation statements)

References 20 publications

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“…It has recently been shown that Tyr-198 forms a cationinteraction with the positive amine of GABA (15), and thus we can confidently locate this part of the GABA molecule close to this residue. The aim of this study was to locate the other end of GABA, the carboxylate group, in the binding site.…”

Section: Gabamentioning

confidence: 85%

“…Docking, combined with previous functional studies (15), suggest that the amine of GABA is located here. There are also a number of charged and hydrophilic residues in the binding pocket that have the potential to interact with GABA: Arg-104, His-105, Met-156, Arg-158, Ser-168, Ser-197, Ser-243, and Arg-249.…”

Section: Functional Studies Of Wild Type and Mutant Gaba Cmentioning

confidence: 98%

See 1 more Smart Citation

Locating the Carboxylate Group of GABA in the Homomeric rho GABAA Receptor Ligand-binding Pocket

Harrison¹,

Lummis

2006

Journal of Biological Chemistry

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GABA3 is the major inhibitory neurotransmitter in the mammalian central nervous system (1). It mediates its effects via both ionotropic (GABA A ) and metabotropic (GABA B ) receptors. GABA C receptors are a subfamily of GABA A receptors and are sometimes referred to as GABA receptors, because the first subunit identified from this class of receptor was called 1 (2). These receptors have been separated from "classic" GABA A receptors because of their distinct pharmacological properties;GABA C receptor-mediated responses are not inhibited by bicuculline (the classic competitive GABA A receptor antagonist) nor induced by baclofen (the classic GABA B receptor agonist). In addition, 3-aminopropylphosphinic acid, a potent competitive GABA C receptor antagonist, acts as an agonist at the GABA B receptor and is inactive at the GABA A receptor, and GABA and trans-4-aminocrotonic acid are more potent agonists at GABA C receptors than GABA A or GABA B receptors (3). Thus there is clearly some variation in the structures of the different GABA-binding sites contained in these receptors, although the sequence homology between GABA A and GABA C receptor subunit sequences (Ͼ25%) indicates that their basic structures will be similar (structural homology is estimated at close to 80%) and will be similar to other members of the Cys loop family (4, 5).The lack of detailed structural information available for Cys loop receptors means that homology modeling is currently one of the best approaches to investigate possible molecular interactions between binding site residues and ligands. This approach has been made possible by the availability of the high resolution structure of the acetylcholine binding protein (AChBP), which is homologous to the extracellular domain of the nicotinic ACh receptor (6). Using this as a template, computer-generated models of ligandbinding pockets of Cys loop receptors, combined with previous data from structure-activity studies, have identified important features of these pockets and on the orientation of agonists and antagonists when located in their binding sites (7)(8)(9)(10)(11)(12)(13). Generating an accurate representation of the orientation of GABA in the GABA C receptor-binding site could identify the processes involved in ligand recognition at this receptor and would also assist in drug design; current data indicate that drugs acting on GABA C receptors could possibly be used to treat visual, sleep, and cognitive disorders (4,14).It has recently been shown that Tyr-198 forms a cationinteraction with the positive amine of GABA (15), and thus we can confidently locate this part of the GABA molecule close to this residue. The aim of this study was to locate the other end of GABA, the carboxylate group, in the binding site. This negatively charged end of GABA has been shown to interact with one or more positively charged residues in the GABA A receptor-binding pocket (16), and here we examine the role of positively charged and polar residues that are in or close to GABA in the GABA C receptor-binding...

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Section: Gabamentioning

confidence: 85%

Section: Functional Studies Of Wild Type and Mutant Gaba Cmentioning

confidence: 98%

Locating the Carboxylate Group of GABA in the Homomeric rho GABAA Receptor Ligand-binding Pocket

Harrison¹,

Lummis

2006

Journal of Biological Chemistry

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“…In addition, intersubunit interactions between Y151 (Loop B) of the principal subunit and T54 (Loop D) and S121 (Loop E) of the complementary subunit were induced in the presence of the ligand. The Y151 residue in Loop B is highly conserved and in several LGICs the aromatic side chain has been proposed to be involved in cation-π interaction with the agonist 31,32 .…”

Section: Agonist Binding Rearranges Intersubunit Hydrogen Bonds At Thmentioning

confidence: 99%

Conformational Gating Dynamics in the GluCl Anion-Selective Chloride Channel

Yoluk

Lindahl

Andersson

2015

ACS Chem. Neurosci.

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“…This study provides direct evidence for the occurrence of target-site resistance to a neonicotinoid insecticide [35] , and investigated about the nature of cation-π binding site in the nicotinic receptor and finds that the nicotinic acetylcholine receptor is the prototype ligand-gated ion channel. A number of aromatic amino acids have been identified as contributing to the agonist binding site, suggesting that cation-π interactions may be involved in binding the quaternary ammonium group of the agonist, acetylcholine [36] . The conformation of cholinergic molecules at nicotinic nerve receptors, and finds a correlation of the crystal structure analyses of the potent nicotinic agonists acetylcholine, acetyl-α-methylcholine, lactoylcholine, 1,1-dimethyl-4-phenylpiperazine, and nicotine allows one to determine the conformation of cholinergic agonists relevant to nicotinic nerve receptors [37] .…”

Section: Nicotinic Receptor Structurementioning

confidence: 99%