Locating GABA in GABA receptor binding sites

2009 ◽  
Vol 37 (6) ◽  
pp. 1343-1346 ◽  
Author(s):  
Sarah C.R. Lummis
Keyword(s):  
Ion Channels ◽  
Ligand Binding ◽  
Binding Site ◽  
Receptor Binding ◽  
Functional Data ◽  
Binding Sites ◽  
Gaba Receptor ◽  
Aminobutyric Acid ◽  
Specific Interactions ◽  
Gabac Receptors

The Cys-loop family of ligand-gated ion channels contains both vertebrate and invertebrate members that are activated by GABA (γ-aminobutyric acid). Many of the residues that are critical for ligand binding have been identified in vertebrate GABAA and GABAC receptors, and specific interactions between GABA and some of these residues have been determined. In the present paper, I show how a cation–π interaction for one of the binding site residues has allowed the production of models of GABA docked into the binding site, and these orientations are supported by mutagenesis and functional data. Surprisingly, however, the residue that forms the cation–π interaction is not conserved, suggesting that GABA occupies subtly different locations even in such closely related receptors.

scholarly journals Positive co-operative binding at two weak lysine-binding sites governs the Glu-plasminogen conformational change

1992 ◽  
Vol 285 (2) ◽  
pp. 419-425 ◽  
Author(s):  
U Christensen ◽  
L Mølgaard
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Conformational Change ◽  
Conformational Changes ◽  
Binding Sites ◽  
High Specificity ◽  
Stopped Flow ◽  
Protein Fluorescence ◽  
Lysine Residues ◽  
Kinetics Of

The kinetics of a series of Glu-plasminogen ligand-binding processes were investigated at pH 7.8 and 25 degrees C (in 0.1 M-NaCl). The ligands include compounds analogous to C-terminal lysine residues and to normal lysine residues. Changes of the Glu-plasminogen protein fluorescence were measured in a stopped-flow instrument as a function of time after rapid mixing of Glu-plasminogen and ligand at various concentrations. Large positive fluorescence changes (approximately 10%) accompany the ligand-induced conformational changes of Glu-plasminogen resulting from binding at weak lysine-binding sites. Detailed studies of the concentration-dependencies of the equilibrium signals and the rate constants of the process induced by various ligands showed the conformational change to involve two sites in a concerted positive co-operative process with three steps: (i) binding of a ligand at a very weak lysine-binding site that preferentially, but not exclusively, binds C-terminal-type lysine ligands, (ii) the rate-determining actual-conformational-change step and (iii) binding of one more lysine ligand at a second weak lysine-binding site that then binds the ligand more tightly. Further, totally independent initial small negative fluorescence changes (approximately 2-4%) corresponding to binding at the strong lysine-binding site of kringle 1 [Sottrup-Jensen, Claeys, Zajdel, Petersen & Magnusson (1978) Prog. Chem. Fibrinolysis Thrombolysis 3, 191-209] were observed for the C-terminal-type ligands. The finding that the conformational change in Glu-plasminogen involves two weak lysine-binding sites indicates that the effect cannot be assigned to any single kringle and that the problem of whether kringle 4 or kringle 5 is responsible for the process resolves itself. Probably kringle 4 and 5 are both participating. The involvement of two lysine binding-sites further makes the high specificity of Glu-plasminogen effectors more conceivable.

Generation of an agonistic binding site for blockers of the M3 muscarinic acetylcholine receptor

2008 ◽  
Vol 412 (1) ◽  
pp. 103-112 ◽  
Author(s):  
Doreen Thor ◽  
Angela Schulz ◽  
Thomas Hermsdorf ◽  
Torsten Schöneberg
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Binding Sites ◽  
Expression System ◽  
Muscarinic Acetylcholine Receptor ◽  
Intracellular Loop ◽  
Inverse Agonists ◽  
Yeast Expression System ◽  
High Affinity

GPCRs (G-protein-coupled receptors) exist in a spontaneous equilibrium between active and inactive conformations that are stabilized by agonists and inverse agonists respectively. Because ligand binding of agonists and inverse agonists often occurs in a competitive manner, one can assume an overlap between both binding sites. Only a few studies report mutations in GPCRs that convert receptor blockers into agonists by unknown mechanisms. Taking advantage of a genetically modified yeast strain, we screened libraries of mutant M3Rs {M3 mAChRs [muscarinic ACh (acetylcholine) receptors)]} and identified 13 mutants which could be activated by atropine (EC50 0.3–10 μM), an inverse agonist on wild-type M3R. Many of the mutations sensitizing M3R to atropine activation were located at the junction of intracellular loop 3 and helix 6, a region known to be involved in G-protein coupling. In addition to atropine, the pharmacological switch was found for other M3R blockers such as scopolamine, pirenzepine and oxybutynine. However, atropine functions as an agonist on the mutant M3R only when expressed in yeast, but not in mammalian COS-7 cells, although high-affinity ligand binding was comparable in both expression systems. Interestingly, we found that atropine still blocks carbachol-induced activation of the M3R mutants in the yeast expression system by binding at the high-affinity-binding site (Ki ∼10 nM). Our results indicate that blocker-to-agonist converting mutations enable atropine to function as both agonist and antagonist by interaction with two functionally distinct binding sites.

A Novel Gaba Receptor on Central Neurones

1980 ◽  
Vol 25 (4) ◽  
pp. S3-S11 ◽  
Author(s):  
N. G. Bowery ◽  
A. Doble ◽  
D. R. Hill ◽  
A. L. Hudson ◽  
J. Shaw ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Ligand Binding ◽  
Gaba Receptor ◽  
Membrane Conductance ◽  
Chloride Ions ◽  
Aminobutyric Acid ◽  
The Novel ◽  
Inhibitory Neurotransmitter ◽  
Gaba Analogues ◽  
Potent Agonist

The features of γ-aminobutyric acid (GABA) as an inhibitory neurotransmitter are described, together with those of its receptor as defined by both iontophoretic and radiolabelled ligand binding techniques. Evidence is presented supporting the existence of a second GABA receptor at both peripheral nerve endings and within the CNS. At the classical receptor, GABA can produce a depolarisation of the ganglion cell body or mediate hyperpolarisation within the CNS by increasing membrane conductance to chloride ions. At this second receptor GABA acts in a bicuculline-insensitive manner to reduce neurotransmitter outflow. Many GABA analogues active at the classical receptor are inactive at the second receptor but by contrast baclofen which is inactive at the classical receptor is a potent agonist at the novel site.

Structural elements involved in activation of the γ-aminobutyric acid type A (GABAA) receptor

2004 ◽  
Vol 32 (3) ◽  
pp. 540-546 ◽  
Author(s):  
T.L. Kash ◽  
J.R. Trudell ◽  
N.L. Harrison
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Binding Site ◽  
Type A ◽  
Aminobutyric Acid ◽  
Structural Elements ◽  
Agonist Binding ◽  
Acid Type ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Ligand-gated ion channels function as rapid signal transducers, converting chemical signals (in the form of neurotransmitters) into electrical signals in the postsynaptic neuron. This is achieved by the recognition of neurotransmitter at its specific-binding sites, which then triggers the opening of an ion channel (‘gating’). For this to occur rapidly (<1 ms), there must be an efficient coupling between the agonist-binding site and the gate, located more than 30 Å (1 Å=0.1 nm) away. Whereas a great deal of progress has been made in elucidating the structure and function of both the agonist-binding site and the ion permeation pathway in ligand-gated ion channels, our knowledge of the coupling mechanism between these domains has been limited. In this review, we summarize recent studies of the agonist-binding site and the ion channel in the γ-aminobutyric acid type A receptor, and discuss those structural elements that may mediate coupling between them. We will also consider some possible molecular mechanisms of receptor activation.

Gamma-aminobutyric acid (GABA) receptor binding selectively depleted by viral induced granule cell loss in hamster cerebellum

1976 ◽  
Vol 105 (2) ◽  
pp. 365-371 ◽  
Author(s):  
Rabi Simantov ◽  
Mary Lou Oster-Granite ◽  
Robert M. Herndon ◽  
Solomon H. Snyder
Keyword(s):  
Receptor Binding ◽  
Granule Cell ◽  
Gaba Receptor ◽  
Cell Loss ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid

5-(Piperidin-4-yl)-3-Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ-Aminobutyric Acid Type A Receptor Binding Site

ChemMedChem ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. 2475-2485 ◽  
Author(s):  
Jacob Krall ◽  
Kenneth T. Kongstad ◽  
Birgitte Nielsen ◽  
Troels E. Sørensen ◽  
Thomas Balle ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Binding Site ◽  
Acid Type ◽  
Novel Scaffold

scholarly journals PDBspheres - a method for finding 3D similarities in local regions in proteins

2022 ◽  
Author(s):  
Adam Zemla ◽  
Jonathan E. Allen ◽  
Dan Kirshner ◽  
Felice C. Lightstone
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Binding Sites ◽  
Protein Structures ◽  
Data Bank ◽  
Structure Alignment ◽  
Alignment Algorithm ◽  
Site Prediction ◽  
Binding Site Prediction ◽  
Structure Similarity

We present a structure-based method for finding and evaluating structural similarities in protein regions relevant to ligand binding. PDBspheres comprises an exhaustive library of protein structure regions (spheres) adjacent to complexed ligands derived from the Protein Data Bank (PDB), along with methods to find and evaluate structural matches between a protein of interest and spheres in the library. Currently, PDBspheres library contains more than 2 million spheres, organized to facilitate searches by sequence and/or structure similarity of protein-ligand binding sites or interfaces between interacting molecules. PDBspheres uses the LGA structure alignment algorithm as the main engine for detecting structure similarities between the protein of interest and library spheres. An all-atom structure similarity metric ensures that sidechain placement is taken into account in the PDBspheres primary assessment of confidence in structural matches. In this paper, we (1) describe the PDBspheres method, (2) demonstrate how PDBspheres can be used to detect and characterize binding sites in protein structures, (3) compare PDBspheres use for binding site prediction with seven other binding site prediction methods using a curated dataset of 2,528 ligand-bound and ligand-free crystal structures, and (4) use PDBspheres to cluster pockets and assess structural similarities among protein binding sites of the 4,876 structures in the refined set of PDBbind 2019 dataset. The PDBspheres library is made publicly available for download at https://proteinmodel.org/AS2TS/PDBspheres

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