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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular actions of smoking cessation drugs at α4p2 nicotinic receptors defined in crystal structures of a homologous binding protein
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Molecular actions of smoking cessation drugs at α4p2 nicotinic receptors defined in crystal structures of a homologous binding protein

机译：戒烟药物对同源结合蛋白晶体结构中定义的α4p2烟碱受体的分子作用

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摘要

Partial agonists of the a4p2 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 α4(β2 nAChRs. We then used structure-guided mutagenesis and electro-physiological 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.
机译：a4p2烟碱乙酰胆碱受体（nAChR）的部分激动剂，例如缬尼克兰，在治疗中用于戒烟治疗。这些药物的治疗作用来自基本的分子作用，即对α4β2nAChRs脱敏并以较高的亲和力诱导通道开放，但在完全相同的受体占有率下比完全激动剂的功效低。在这里，我们报道了从头状小肠小肠Ct-AChBP的独特乙酰胆碱结合蛋白（AChBP）的X射线晶体结构，与伐尼克兰或肝油碱（均为部分激动剂）复合。这些结构突显了这些配体的分子识别结构，表明了可能在α4（β2nAChRs）中介导其分子作用的接触残基，然后我们使用了结构指导的诱变和电生理记录来精确地确定缬草碱与药物残留的关键相互作用。我们观察到环D和E中的残基是脱敏和通道开放的分子决定因素，部分激动剂伐尼克兰的功效有限，共同研究了nAChRs对戒烟药物的分子识别结构上下文。

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  • 作者

    Bert Billen; Radovan Spurny; Marijke Brams; Rene van Elk; Soledad Valera-Kummer; Jerrel L. Yakel; Thomas Voets; Daniel Bertrand; August B. Smit; Chris Ulens;

  • 作者单位

    Laboratory of Structural Neurobiology, KU Leuven, 3000 Leuven, Belgium;

    Laboratory of Structural Neurobiology, KU Leuven, 3000 Leuven, Belgium;

    Laboratory of Structural Neurobiology, KU Leuven, 3000 Leuven, Belgium;

    Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV, Amsterdam, The Netherlands;

    HiQScreen, 1211 Geneva, Switzerland;

    Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 22709;

    Laboratory of lo'n Channel Research, KU Leuven, 3000 Leuven, Belgium;

    HiQScreen, 1211 Geneva, Switzerland;

    Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081 HV, Amsterdam, The Netherlands;

    Laboratory of Structural Neurobiology, KU Leuven, 3000 Leuven, Belgium;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    addiction; cys-loop receptor; ligand-gated ion channel;

    机译：瘾;半胱氨酸环受体;配体门控离子通道;

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