Evaluation of Diverse 伪/尾-Backbone Patterns for Functional 伪-Helix Mimicry: Analogues of the Bim BH3 Domain

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• 作者：Melissa D. Boersma ; Holly S. Haase ; Kimberly J. Peterson-Kaufman ; Erinna F. Lee ; Oliver B. Clarke ; Peter M. Colman ; Brian J. Smith ; W. Seth Horne ; W. Douglas Fairlie ; Samuel H. Gellman
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：January 11, 2012
• 年：2012
• 卷：134
• 期：1
• 页码：315-323
• 全文大小：1055K
• 年卷期：v.134,no.1(January 11, 2012)
• ISSN：1520-5126

文摘

Peptidic oligomers that contain both 伪- and 尾-amino acid residues, in regular patterns throughout the backbone, are emerging as structural mimics of 伪-helix-forming conventional peptides (composed exclusively of 伪-amino acid residues). Here we describe a comprehensive evaluation of diverse 伪/尾-peptide homologues of the Bim BH3 domain in terms of their ability to bind to the BH3-recognition sites on two partner proteins, Bcl-x_L and Mcl-1. These proteins are members of the anti-apoptotic Bcl-2 family, and both bind tightly to the Bim BH3 domain itself. All 伪/尾-peptide homologues retain the side-chain sequence of the Bim BH3 domain, but each homologue contains periodic 伪-residue 鈫?尾³-residue substitutions. Previous work has shown that the 伪伪尾伪伪伪尾 pattern, which aligns the 尾³-residues in a 鈥檚tripe鈥?along one side of the helix, can support functional 伪-helix mimicry, and the results reported here strengthen this conclusion. The present study provides the first evaluation of functional mimicry by 伪伪尾 and 伪伪伪尾 patterns, which cause the 尾³-residues to spiral around the helix periphery. We find that the 伪伪伪尾 pattern can support effective mimicry of the Bim BH3 domain, as manifested by the crystal structure of an 伪/尾-peptide bound to Bcl-x_L, affinity for a variety of Bcl-2 family proteins, and induction of apoptotic signaling in mouse embryonic fibroblast extracts. The best 伪伪伪尾 homologue shows substantial protection from proteolytic degradation relative to the Bim BH3 伪-peptide.