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Structural studies on the ligand sti...

Xu, Rui.

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Structural studies on the ligand stimulation of nicotinic acetylcholine receptor alpha9.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Structural studies on the ligand stimulation of nicotinic acetylcholine receptor alpha9./
Author:	Xu, Rui.
Description:	152 p.
Notes:	Adviser: Wayne A. Hendrickson.
Contained By:	Dissertation Abstracts International68-09B.
Subject:	Biology, Neuroscience. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3285206
ISBN:	9780549273172

Structural studies on the ligand stimulation of nicotinic acetylcholine receptor alpha9.
Xu, Rui.

Structural studies on the ligand stimulation of nicotinic acetylcholine receptor alpha9. - 152 p.

Adviser: Wayne A. Hendrickson.

Thesis (Ph.D.)--Columbia University, 2007.

Nicotinic acetylcholine receptor (nAChR) is a member of the Cys-loop ligand-gated ion channel (LGIC) superfamily, which also includes 5-hydroxytryptamine (5-HT3), gamma-aminobutyric acid (GABA) and glycine receptors. LGICs function on a timescale of milliseconds upon binding of neurotransmitters and mediate fast synaptic transmission in the nervous system. nAChRs are important therapeutic drug targets for treatments of nicotine addiction and multiple neurological diseases including schizophrenia, Alzheimer's disease and Parkinson's disease. They are pentameric complexes formed by homologous subunits with a selective ion pore in the centre and each subunit comprises a large N-terminal extracellular ligand-binding domain followed by a channel forming transmembrane domain and an intracellular domain. The ligand-binding domain of nAChR harbours neurotransmitter-binding site and is the key for the understanding of ligand induced channel gating. In this thesis, I report the crystal structures of chicken alpha9 extracellular ligand-binding domain in complex with multiple nicotinic antagonists and agonists. The alpha9 protomer displays a beta rich structure with conserved major determinants for receptor-ligand interactions. Comparison of the structures reveals that agonist binding induces contraction of the ligand binding site and domain bending of the ligand-binding domain. Based on this finding, we propose a "twisted contraction" mechanism of the ligand-binding domain complex in receptor during gating. Unique structural motifs, including the signature Cys-loop and an electrostatic triad mediated by Arg210, Glu47, Asp140 and Glu177, are essential for signal propagation from ligand binding to channel opening. The information provided by the structures is essential for the exploration of the receptor gating mechanism and provides a great start point for homology modelling and drug design of the Cys-loop LGIC receptor superfamily.

ISBN: 9780549273172Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Structural studies on the ligand stimulation of nicotinic acetylcholine receptor alpha9.
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100 1 $a Xu, Rui. $3 1262927
245 1 0 $a Structural studies on the ligand stimulation of nicotinic acetylcholine receptor alpha9.
300 $a 152 p.
500 $a Adviser: Wayne A. Hendrickson.
500 $a Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5794.
502 $a Thesis (Ph.D.)--Columbia University, 2007.
520 $a Nicotinic acetylcholine receptor (nAChR) is a member of the Cys-loop ligand-gated ion channel (LGIC) superfamily, which also includes 5-hydroxytryptamine (5-HT3), gamma-aminobutyric acid (GABA) and glycine receptors. LGICs function on a timescale of milliseconds upon binding of neurotransmitters and mediate fast synaptic transmission in the nervous system. nAChRs are important therapeutic drug targets for treatments of nicotine addiction and multiple neurological diseases including schizophrenia, Alzheimer's disease and Parkinson's disease. They are pentameric complexes formed by homologous subunits with a selective ion pore in the centre and each subunit comprises a large N-terminal extracellular ligand-binding domain followed by a channel forming transmembrane domain and an intracellular domain. The ligand-binding domain of nAChR harbours neurotransmitter-binding site and is the key for the understanding of ligand induced channel gating. In this thesis, I report the crystal structures of chicken alpha9 extracellular ligand-binding domain in complex with multiple nicotinic antagonists and agonists. The alpha9 protomer displays a beta rich structure with conserved major determinants for receptor-ligand interactions. Comparison of the structures reveals that agonist binding induces contraction of the ligand binding site and domain bending of the ligand-binding domain. Based on this finding, we propose a "twisted contraction" mechanism of the ligand-binding domain complex in receptor during gating. Unique structural motifs, including the signature Cys-loop and an electrostatic triad mediated by Arg210, Glu47, Asp140 and Glu177, are essential for signal propagation from ligand binding to channel opening. The information provided by the structures is essential for the exploration of the receptor gating mechanism and provides a great start point for homology modelling and drug design of the Cys-loop LGIC receptor superfamily.
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650 4 $a Biology, Neuroscience. $3 1017680
650 4 $a Biophysics, General. $3 1019105
650 4 $a Health Sciences, Pharmacology. $3 1017717
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