戒烟药物对α4β2尼古丁受体的分子作用机制：同源结合蛋白的晶体结构
2012/07/05
摘要
α4β2尼古丁乙酰胆碱受体（nAChR）部分激动剂（如伐尼克兰）常用于戒烟。这些药物的治疗作用来自于其基础的分子作用机制，主要是使α4β2 nAChRs 脱敏，因高亲和力而诱导通道开放，但这些药物的效果不及完全激动剂。本研究从来自环节动物小头虫的特殊乙酰胆碱结合蛋白（AChBP）---Ct-AChBP的X线晶体结构入手，研究伐尼克兰或络贝林的作用。显示了这些配体进行分子识别的结构，表明接触残基介导了对α4β2 nAChRs的分子作用。随后，采用结构指导的致突变和电生理记录，检测伐尼克兰与α4β2 nAChRs结合位点上互补面残基的相互作用。结果显示，环D和E上的残基是部分激动剂伐尼克兰导致脱敏和通道开放的决定因素，但效果有限。总之，本研究从结构上分析了戒烟药物与nAChRs相互作用的分子机制。
（陈欣 审校）
Proc Natl Acad Sci U S A. 2012 May 22. [Epub ahead of print]
Proc Natl Acad Sci U S A. 2012 May 22. [Epub ahead of print]
Billen B, Spurny R, Brams M, van Elk R, Valera-Kummer S, Yakel JL, Voets T, Bertrand D, Smit AB, Ulens C.
Source
Laboratory of Structural Neurobiology, KU Leuven, 3000 Leuven, Belgium.
Abstract
Partial agonists of the α4β2 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 α4β2 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 α4β2 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 α4β2 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.
Laboratory of Structural Neurobiology, KU Leuven, 3000 Leuven, Belgium.
Abstract
Partial agonists of the α4β2 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 α4β2 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 α4β2 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 α4β2 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.
Proc Natl Acad Sci U S A. 2012 May 22. [Epub ahead of print]
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