期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 130, 期 26, 页码 8326-8336出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja8004495
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Whereas the C-terminal fragment of neuropeptide Y (NPY) has been structurally well-defined both in solution and as membrane-bound, detailed structural information regarding the proline-rich N-terminus is still missing. The systematic variation of each position by a conformationally constrained pyridone dipeptide building block within the amino terminal segment of NPY leads to a systematic receptor subtype selectivity of the neuropeptide. Thereby, the systematic dipeptide scan proved superior to the traditional L-Ala scan because it showed how to modify the N-terminus in order to obtain increasingly more Y(1) or Y(5) receptor selective ligands. NMR and CD spectroscopic analyses were used to characterize the stepwise rigidification of the N-terminus of NPY when up to three dipeptide building blocks were incorporated by solid-phase peptide synthesis. The pyridone dipeptide increases the hydrophobicity of the amino terminus of NPY, and this allows the tuning of the membrane affinity of NPY. The amphiphilic C-terminal helix of 3-fold-substituted NPY thus becomes visible by selective line broadening in the (1)H NMR. Accordingly, we could structurally characterize protein segments that are too flexible for other methods.
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