Nakamura M, Niwa Y, Ishida Y, Kohno T, Sato K, Oba Y, Nakamura H
Graduate School of Bioagricultural Sciences, Nagoya University, Japan.
FEBS Lett. 2001 Aug 10;503(1):107-10. doi: 10.1016/s0014-5793(01)02714-4.
mu-Conotoxin GIIIA, a peptide toxin isolated from the marine snail Conus geographus, preferentially blocks skeletal muscle sodium channels in vertebrates. In this study, analogs of mu-conotoxin GIIIA in which essential Arg-13 was replaced with arginine analogs consisting of a piperidyl framework to regulate length and direction of the side chain were synthesized. Synthesized analogs exhibited similar CD and NMR spectra to that of GIIIA, suggesting a three-dimensional structure identical to that of the native toxin. The biological activities of piperidyl analogs were decreased or lost despite the small change in the side chain of Arg-13. The investigated structure-activity relationships in inhibiting electrically stimulated muscle contraction suggest that the guanidinium group at amino acid position 13 interacts best when spaced with three to four carbons and placed in a vertical direction from the peptide loop. Thus, the position of the guanidinium group at Arg-13 of GIIIA must be located in a certain range for its strong interaction with the channel protein.
μ-芋螺毒素GIIIA是一种从海洋蜗牛地纹芋螺中分离出的肽类毒素，它优先阻断脊椎动物骨骼肌的钠通道。在本研究中，合成了μ-芋螺毒素GIIIA的类似物，其中关键的精氨酸-13被由哌啶基骨架组成的精氨酸类似物取代，以调节侧链的长度和方向。合成的类似物表现出与GIIIA相似的圆二色光谱和核磁共振光谱，表明其三维结构与天然毒素相同。尽管精氨酸-13的侧链变化很小，但哌啶基类似物的生物活性却降低或丧失了。所研究的抑制电刺激肌肉收缩的构效关系表明，氨基酸位置13处的胍基在与三到四个碳原子间隔并从肽环垂直放置时相互作用最佳。因此，GIIIA中精氨酸-13处胍基的位置必须位于一定范围内，才能与通道蛋白发生强烈相互作用。
