-Turn Mimetics: Short Peptide -Helices Composed of Cyclic Metall

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• 作者：Michael J. Kelso ; René ; e L. Beyer ; Huy N. Hoang ; Ami S. Lakdawala ; James P. Snyder ; Warren V. Oliver ; Tom A. Robertson ; Trevor G. Appleton ; and David P. Fairlie
• 刊名：Journal of the American Chemical Society
• 出版年：2004
• 出版时间：April 21, 2004
• 年：2004
• 卷：126
• 期：15
• 页码：4828 - 4842
• 全文大小：637K
• 年卷期：v.126,no.15(April 21, 2004)
• ISSN：1520-5126

文摘

SRC="/images/gifchars/alpha.gif" BORDER=0>-Helices are key structural components of proteins and important recognition motifs in biology.Short peptides (s/entities/le.gif">15 residues) corresponding to these helical sequences are rarely helical away from theirstabilizing protein environments. New techniques for stabilizing short peptide helices could be valuable forstudying protein folding, modeling proteins, creating artificial proteins, and may aid the design of inhibitorsor mimics of protein function. This study reports the facile incorporation of 3- and 4-s/gifchars/alpha.gif" BORDER=0> turns in 10-15 residuepeptides through formation in situ of multiple cyclic metallopeptide modules [Pd(en)(H*XXXH*)]²⁺. Thenonhelical peptides Ac-H*ELTH*H*VTDH*-NH₂ (1), Ac-H*ELTH*AVTDYH*ELTH*-NH₂ (2), and Ac-H*AAAH*H*ELTH*H*VTDH*-NH₂ (3) (H* is histidine-methylated at imidazole-N3) react in N,N-dimethylformamide (DMF) or water with 2, 2, and 3 molar equivalents, respectively, of [Pd(en)(NO₃)₂] to formexclusively [Pd₂(en)₂(Ac-H*ELTH*H*VTDH*-NH₂)]⁴⁺ (4), [Pd₂(en)₂(Ac-H*ELTH*AVTDYH*ELTH*-NH₂)]⁴⁺ (5),and [Pd₃(en)₃(Ac-H*AAAH*H*ELTH*H*VTDH*-NH₂)]⁶⁺ (6), characterized by mass spectrometry, 1D and2D ¹H- and 1D ¹⁵N-NMR spectroscopy. Despite the presence of multiple histidines and other possiblemetal-binding residues in these peptides, 2D ¹H NMR spectra reveal that Pd(en)²⁺ is remarkably specificin coordinating to imidazole-N1 of only (i, i + 4) pairs of histidines (i.e., only those separated by threeamino acids), resulting in 4-6 made up of cyclic metallopentapeptide modules ([Pd(en)(H*XXXH*)]²⁺)_n,n = 2, 2, 3, respectively, each cycle being a 22-membered ring. We have previously shown that a singlemetallopentapeptide can nucleate s/gifchars/alpha.gif" BORDER=0>-helicity (Kelso et al., Angew. Chem., Int. Ed. 2003, 42, 421-424.).We now demonstrate its use as an s/gifchars/alpha.gif" BORDER=0>-turn-mimicking module for the facile conversion of unstructured shortpeptides into helices of macrocycles and provide 1D and 2D NMR spectroscopic data, structure calculationsvia XPLOR and NMR analysis of molecular flexibility in solution (NAMFIS), and CD spectra in support ofthe s/gifchars/alpha.gif" BORDER=0>-helical nature of these monomeric metallopeptides in solution.