共 39 条
Molecular actions of smoking cessation drugs at α4β2 nicotinic receptors defined in crystal structures of a homologous binding protein
被引:61
作者:

Billen, Bert
论文数: 0 引用数: 0
h-index: 0
机构:
Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

Spurny, Radovan
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Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

Brams, Marijke
论文数: 0 引用数: 0
h-index: 0
机构:
Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

van Elk, Rene
论文数: 0 引用数: 0
h-index: 0
机构:
Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, NL-1081 HV Amsterdam, Netherlands Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

Valera-Kummer, Soledad
论文数: 0 引用数: 0
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机构:
HiQScreen, CH-1211 Geneva, Switzerland Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

Yakel, Jerrel L.
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h-index: 0
机构:
Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

Voets, Thomas
论文数: 0 引用数: 0
h-index: 0
机构:
Katholieke Univ Leuven, Lab Ion Channel Res, B-3000 Louvain, Belgium Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

Bertrand, Daniel
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HiQScreen, CH-1211 Geneva, Switzerland Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

Smit, August B.
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h-index: 0
机构:
Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, NL-1081 HV Amsterdam, Netherlands Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium

Ulens, Chris
论文数: 0 引用数: 0
h-index: 0
机构:
Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium
机构:
[1] Katholieke Univ Leuven, Lab Struct Neurobiol, B-3000 Louvain, Belgium
[2] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, NL-1081 HV Amsterdam, Netherlands
[3] HiQScreen, CH-1211 Geneva, Switzerland
[4] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA
[5] Katholieke Univ Leuven, Lab Ion Channel Res, B-3000 Louvain, Belgium
来源:
基金:
美国国家卫生研究院;
关键词:
addiction;
cys-loop receptor;
ligand-gated ion channel;
GATED ION-CHANNEL;
X-RAY-STRUCTURE;
ACETYLCHOLINE-RECEPTORS;
PARTIAL AGONIST;
VARENICLINE;
DEPENDENCE;
ACTIVATION;
RESOLUTION;
SUBUNITS;
D O I:
10.1073/pnas.1116397109
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
Partial agonists of the alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR), such as varenicline, are therapeutically used in smoking cessation treatment. These drugs derive their therapeutic effect from fundamental molecular actions, which are to desensitize alpha 4 beta 2 nAChRs and induce channel opening with higher affinity, but lower efficacy than a full agonist at equal receptor occupancy. Here, we report X-ray crystal structures of a unique acetylcholine binding protein (AChBP) from the annelid Capitella teleta, Ct-AChBP, in complex with varenicline or lobeline, which are both partial agonists. These structures highlight the architecture for molecular recognition of these ligands, indicating the contact residues that potentially mediate their molecular actions in alpha 4 beta 2 nAChRs. We then used structure-guided mutagenesis and electrophysiological recordings to pinpoint crucial interactions of varenicline with residues on the complementary face of the binding site in alpha 4 beta 2 nAChRs. We observe that residues in loops D and E are molecular determinants of desensitization and channel opening with limited efficacy by the partial agonist varenicline. Together, this study analyzes molecular recognition of smoking cessation drugs by nAChRs in a structural context.
引用
收藏
页码:9173 / 9178
页数:6
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:9459-9464

Gallivan, JP
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CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA

Dougherty, DA
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CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA