Structural models of the nicotinic acetylcholine receptor and its toxin-binding sites

Guy, H. Robert

doi:10.1007/bf00710680

Cited by 9 publications

(3 citation statements)

References 48 publications

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“…They further propose that one of the hydrophobic membrane-spanning segments may form the cation channel. More detailed, atomic models for parts of AcChoR also have been proposed (34)(35)(36), though objective bases for evaluating the models are not presented.…”

Section: Discussionmentioning

confidence: 99%

Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.

Finer-Moore¹,

Stroud²

1984

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

469

157

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Fourier analysis of the hydrophobicities of the acetylcholine receptor subunit sequences reveals regions of amphipathic secondary structure. Prediction of a consensus secondary structure based on this analysis and on an empirical prediction method leads to a testable hypothesis about how the ion channel is formed and might function. Knowledge of the three-dimensional structure of acetylcholine receptors is consistent with features of the model proposed and provides some constraints.The acetylcholine receptor (AcChoR) is an '-'250-kilodalton (kDa) complex of five homologous glycoprotein subunits in stoichiometry a2P3y8 (1)(2)(3). The four subunits each contain four hydrophobic stretches of at least 20-25 contiguous residues (4-9). The structural similarity of the five subunits and the transmembrane orientation of secondary structural features (10) imply that they surround the central ion channel like staves (11). This is the simplest arrangement that preserves quasi-equivalent interactions at the subunit interfaces. Huang et al. (12) conclude that the channel is a waterfilled pore containing hydrogen-accepting groups and at least one negatively charged site. Lewis and Stevens (13) calculated the simplest potential energy surface that can account for electrophysiological data (14). Their profile is characterized by two energy barriers separated by a shallow negative energy well, which Horn and Stevens (15) hypothesize results from one or more negatively charged sites within the channel. The dependence of conduction upon ion size for both monovalent and divalent cations has led Lewis and Stevens to conclude (i) that the ion channel environment is similar to that of free water, (ii) that the ion channel may be lined with hydrophilic residues, but (iii) that ion selectivity does not result from direct interaction of ions with amino acid side chains (16).Inspection of the y-subunit sequence for regions that might interface with a hydrophobic domain and form a hydrophilic wall of the ion channel identifies regions in which charged or very hydrophilic residues are interspersed with neutral or hydrophobic residues in a periodic fashion characteristic of regular secondary structures. This observation prompted us to quantitate the local periodicity in the hydrophobicities of the primary structures of all subunits by Fourier analysis. McLachlan has discussed Fourier analysis as a means of identifying periodic properties of amino acid sequences (17). We used Fourier analysis for amphipathic secondary structure correlation together with a secondary structure prediction method for the -75% sequence external to the bilayer and separate evidence for oriented helices in the transmembrane regions to develop an overall structural scheme. The overall predictions gain statistical significance from the congruence of all four subunit types and are consistent with the low-resolution, three-dimensional structure of AcChoR. METHODSThe premise for the analytic method is that regular secondary structural features located at an inter...

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Section: Discussionmentioning

confidence: 99%

Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.

Finer-Moore¹,

Stroud²

1984

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

469

157

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“…[145][146][147][148] Putting together all the evidence coming from X-ray diffraction, photoaffinity labeling, and mutagenesis studies, researchers have tried to build structural models of the neurotransmitter binding site. [149][150][151] Most recently, homology modeling techniques have been used, choosing as a template the enzyme AChE, a protein with known three-dimensional structure which recognizes the same neurotransmitter ACh, 152 or the blue copper binding protein plastocyanine which shows structural similarity with the extracellular domain of the nAChR a subunits. 153 The greatest improvement in the modelling of the neurotransmitter binding site has come after the discovery of a glia-derived AChBP protein, 144 whose X-ray structure reveals a striking resemblance to the nAChR.…”

Section: B I N D I N G S I T E M O D E L Smentioning

confidence: 99%

Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications

Romanelli

Gualtieri

2003

Medicinal Research Reviews

111

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Discovery of the important role played by nicotinic acetylcholine receptors (nAChRs) in several CNS disorders has called attention to these membrane proteins and to ligands able to modulate their functions. The existence of different subtypes at multiple levels has complicated the understanding of this receptor's physiological role, but at the same time has increased the efforts to discover selective compounds in order to improve the pharmacological characterization of this kind of receptor and to make the possible therapeutical use of its modulators safer. This review focuses on the structure of new ligands for nAChRs, agonists, antagonists and allosteric modulators, and on their possible applications.

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“…Several authors have proposed models for the ABS [Smithies, 1980;Guy, 1981;Kosower, 1983;Noda et al, 1982;and Numa et al, 1983; Smart et al, 19841.…”

Section: Comparison With Other Modelsmentioning

confidence: 99%

A model for the acetylcholine binding site of the nicotinic acetylcholine receptor

Luyten

1986

J of Neuroscience Research

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A detailed model for the acetylcholine binding site on the nicotinic acetylcholine receptor is proposed. It is derived from assumptions based on existing biochemical, structural, and pharmacological data, combined with molecular modeling and principles of protein evolution and architecture. Acetylcholine is proposed to fit into a pocket on one face of an antiparallel beta-pleated sheet formed by residues 128-142 on the alpha-subunit. This sheet is flexible yet stable, in part because of a double cystine bridge at its end. Asp138, Thr133, and Gln140 provide a ring of negative charges around the quaternary ammonium group of acetylcholine, Ile131 and alkane segments of the other residues in the binding site provide hydrophobic interactions, and Gln140 provides a hydrogen bond for acetylcholine's carbonyl group; Glu129 would form part of the second anionic subsite for the bis-quaternary ammonium compounds and curares. The model is compatible with the available evidence pertaining to the binding site and with structure-activity relationship studies. It is precise and detailed, thereby making clear predictions, which are directly testable by affinity labeling and site-directed mutagenesis. It should prove useful in the design of such experiments.

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Structural models of the nicotinic acetylcholine receptor and its toxin-binding sites

Cited by 9 publications

References 48 publications

Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.

Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.

Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications

A model for the acetylcholine binding site of the nicotinic acetylcholine receptor

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