Kane Brian E, Nieto Marcelo J, McCurdy Christopher R, Ferguson David M
Department of Medicinal Chemistry and Center for Drug Design, University of Minnesota, MN 55455, USA.
FEBS J. 2006 May;273(9):1966-74. doi: 10.1111/j.1742-4658.2006.05212.x.
Salvinorin A is a potent kappa opioid receptor (KOP) agonist with unique structural and pharmacological properties. This non-nitrogenous ligand lacks nearly all the structural features commonly associated with opioid ligand binding and selectivity. This study explores the structural basis to salvinorin A binding and selectivity using a combination of chimeric and single-point mutant opioid receptors. The experiments were designed based on previous models of salvinorin A that locate the ligand within a pocket formed by transmembrane (TM) II, VI, and VII. More traditional sites of opioid recognition were also explored, including the highly conserved aspartate in TM III (D138) and the KOP selectivity site E297, to determine the role, if any, that these residues play in binding and selectivity. The results indicate that salvinorin A recognizes a cluster of residues in TM II and VII, including Q115, Y119, Y312, Y313, and Y320. Based on the position of these residues within the receptor, and prior study on salvinorin A, a model is proposed that aligns the ligand vertically, between TM II and VII. In this orientation, the ligand spans residues that are spaced one to two turns down the face of the helices within the receptor cavity. The ligand is also in close proximity to EL-2 which, based on chimeric data, is proposed to play an indirect role in salvinorin A binding and selectivity.
萨尔维诺林A是一种强效的κ阿片受体（KOP）激动剂，具有独特的结构和药理特性。这种非含氮配体几乎缺乏所有与阿片类配体结合和选择性相关的常见结构特征。本研究使用嵌合和单点突变阿片受体相结合的方法，探索萨尔维诺林A结合和选择性的结构基础。实验是基于先前的萨尔维诺林A模型设计的，该模型将配体定位在由跨膜（TM）II、VI和VII形成的口袋内。还探索了更传统的阿片类识别位点，包括TM III中高度保守的天冬氨酸（D138）和KOP选择性位点E297，以确定这些残基在结合和选择性中是否发挥作用。结果表明，萨尔维诺林A识别TM II和VII中的一组残基，包括Q115、Y119、Y312、Y313和Y320。基于这些残基在受体中的位置以及对萨尔维诺林A的先前研究，提出了一个模型，该模型将配体垂直排列在TM II和VII之间。在这个方向上，配体跨越受体腔内螺旋表面向下一到两圈间隔的残基。配体也与EL-2紧密相邻，基于嵌合数据，EL-2被认为在萨尔维诺林A的结合和选择性中起间接作用。
