Beck-Sickinger A G, Köppen H, Hoffmann E, Gaida W, Jung G
Institute of Organic Chemistry, University of Tübingen, Germany.
J Recept Res. 1993;13(1-4):215-28. doi: 10.3109/10799899309073656.
A discontinuous 17-amino acid peptide analog of neuropeptide Y (NPY), NPY 1-4-Ahx-25-36 containing 6-aminohexanoic acid instead of the residues 5 to 24, was found to bind preferentially to Y2 subtypes of NPY receptors. In order to further characterize the binding site, three different types of cyclic analogs were synthesized. Firstly lactamisation between residues 2 and 30 led to the most selective Y2-agonist, secondly lactamisation between the N-terminus and residue 31 reduced binding significantly. Thirdly, any cyclization including the C-terminus led to an inactive compound. Circular dichroism revealed different conformations for the three analogs with reduced alpha-helical content in comparison to the linear ana-log. The different conformation of the peptides has been confirmed by molecular dynamics simulations. A model for peptide-receptor interaction is suggested.
一种神经肽Y（NPY）的不连续17氨基酸肽类似物，即NPY 1 - 4 - Ahx - 25 - 36，其中用6 - 氨基己酸取代了5至24位残基，被发现优先结合NPY受体的Y2亚型。为了进一步表征结合位点，合成了三种不同类型的环状类似物。首先，2位和30位残基之间的内酰胺化产生了最具选择性的Y2激动剂；其次，N端和31位残基之间的内酰胺化显著降低了结合。第三，包括C端在内的任何环化都会导致化合物失活。圆二色性显示这三种类似物具有不同的构象，与线性类似物相比，α - 螺旋含量降低。肽的不同构象已通过分子动力学模拟得到证实。提出了一个肽 - 受体相互作用模型。
