Tessmer M R, Kallick D A
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
Biochemistry. 1997 Feb 25;36(8):1971-81. doi: 10.1021/bi961457h.
Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. Interest in designing new ligands to interact at the kappa-opioid receptor is based in part on the desire to circumvent some of the problems associated with mu-opioid ligands such as morphine. The high-resolution structure of dynorphin in an environment which closely resembles its environment in vivo could be considered as an important lead for new drugs. The interactions that occur between dynorphin and a model membrane are potentially important, as peptide hormone activity is thought to be mediated by interactions with the cell membrane. Therefore, we have determined the high-resolution structures of dynorphin in a model membrane. Results from our laboratory have shown the existence of an alpha-helical region in dynorphin from residues Gly3 through Arg9 when bound to perdeuterated dodecylphosphocholine (DPC) micelles. In this report we show that dynorphin is bound to DPC micelles and describe a family of dynorphin structures that is alpha-helical from residues Gly3 through Pro10 and that contains a beta-turn from residues Trp14 through Gln17. A model of interaction with the micelle is also reported and is discussed in the context of hormone action in vivo. The structures were determined with 1D and 2D nuclear magnetic resonance spectroscopy, distance geometry in dihedral angle space, and restrained molecular dynamics simulations.
强啡肽A（1-17）（强啡肽）以高亲和力优先作用于κ-阿片受体，它是该受体的天然内源性配体。设计与κ-阿片受体相互作用的新配体的兴趣部分基于规避与μ-阿片配体（如吗啡）相关的一些问题的愿望。在与体内环境非常相似的环境中强啡肽的高分辨率结构可被视为新药的重要先导。强啡肽与模型膜之间发生的相互作用可能很重要，因为肽激素活性被认为是由与细胞膜的相互作用介导的。因此，我们已经确定了强啡肽在模型膜中的高分辨率结构。我们实验室的结果表明，当与全氘代十二烷基磷酸胆碱（DPC）胶束结合时，强啡肽中从甘氨酸3到精氨酸9的区域存在α-螺旋。在本报告中，我们表明强啡肽与DPC胶束结合，并描述了一个强啡肽结构家族，该家族从甘氨酸3到脯氨酸10是α-螺旋，并且从色氨酸14到谷氨酰胺17包含一个β-转角。还报告了与胶束相互作用的模型，并在体内激素作用的背景下进行了讨论。这些结构是通过一维和二维核磁共振光谱、二面角空间中的距离几何以及受限分子动力学模拟确定的。
