Structural consequences of beta-amino acid preorganization in a self-assembling alpha/beta-peptide: fundamental studies of foldameric helix bundles.
Structural consequences of beta-amino acid preorganization in a self-assembling alpha/beta-peptide: fundamental studies of foldameric helix bundles.
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DOI：
10.1021/ja103543s
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发表时间：
2010-09-08
影响因子：
15
通讯作者：
Gellman, Samuel H.
中科院分区：
文献类型：
--
作者：
Price, Joshua L.;Horne, W. Seth;Gellman, Samuel H.
我们报道了六个具有规则α-残基/α-残基/β-残基（ααβ）主链重复模式的新α/β-肽折叠体的高分辨率晶体结构。这些文件夹都是在水溶液中结晶而成的，在结晶状态下都表现出四螺旋束状的四元结构。这些低聚物是基于经过充分研究的33个残基α-肽GCN4- pli，它是酵母转录因子GCN4二聚化结构域的工程衍生物。GCN4-pLI在溶液中形成稳定的四聚体并结晶为四螺旋束（Harbury等人）。科学1993,262,1401-1407)。先前我们描述了一个由GCN4-pLI通过用同源的β3-氨基酸残基替换每3个α-氨基酸残基而产生的折叠体（这里指定为1）；该ααβ低聚物保留了原α-肽的侧链序列，但主链中含有11个额外的CH2单元，分布均匀（Horne等）。Proc。国家的。学会科学。中国生物医学工程学报，2008,35(5):951 - 9156。尽管主链扩大，1被发现保留形成四聚体四元结构的能力，其中单个分子采用α-螺旋状构象。在这里，我们比较了具有相同ααβ骨架的9个1的类似物，但其中一个或多个灵活的β3氨基酸残基被类似的环状β-残基取代。β3→环置换的动机是提高构象稳定性；然而，先前报道的例子（此处指定为2）的晶体结构揭示了相对于1的螺旋束结构的“口吃”扭曲。本文报道的结果表明，结巴是2的特性，因为所有六个新的α/β-肽都显示未扭曲的四螺旋束四元结构。更广泛地说，我们的结果表明β3→环取代通常在螺旋束四元结构中被很好地容纳，但这种取代在某些情况下可能是不稳定的。
We report high-resolution crystal structures of six new α/β-peptide foldamers that have a regular α-residue/α-residue/β-residue (ααβ) backbone repeat pattern. All of these foldamers were crystallized from aqueous solution, and all display four-helix bundle quaternary structure in the crystalline state. These oligomers are based on the well-studied 33-residue α-peptide GCN4-pLI, which is an engineered derivative of the dimerization domain of GCN4, a yeast transcription factor. GCN4-pLI forms a stable tetramer in solution and crystallizes as a four-helix bundle (Harbury et al. Science 1993, 262, 1401–1407). Previously we described a foldamer (designated 1 here) that was generated from GCN4-pLI by replacing every third α-amino acid residue with the homologous β3-amino acid residue; this ααβ oligomer retains the side chain sequence of the original α-peptide, but the backbone contains 11 additional CH2 units, which are evenly distributed (Horne et al. Proc. Natl. Acad. Sci. USA 2008, 105, 9151–9156). Despite the expanded backbone, 1 was found to retain the ability to form a tetrameric quaternary structure in which the individual molecules adopt an α-helix-like conformation. Here we compare nine analogues of 1 that have the same ααβ backbone but in which one or more of the flexible β3-amino acid residues is/are replaced with an analogous cyclic β-residue. The motivation for β3→cyclic replacements is to enhance conformational stability; however, a crystal structure of the one previously reported example (designated 2 here) revealed a “stammer” distortion of the helix-bundle architecture relative to 1. The results reported here suggest that the stammer is a peculiarity of 2, because all six of the new α/β-peptides display undistorted four-helix bundle quaternary structures. More broadly, our results indicate that β3→cyclic replacements are generally well-accommodated in helix-bundle quaternary structure, but that such replacements can be destabilizing in certain instances.
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影响因子：
--
作者：
Burkoth, TS;Beausoleil, E;Zuckermann, RN
通讯作者：
Zuckermann, RN
影响因子：
56.9
作者：
HARBURY, PB;ZHANG, T;ALBER, T
通讯作者：
ALBER, T
影响因子：
15
作者：
David, Ralf;Guenther, Robert;Beck-Sickinger, Annette G.
通讯作者：
Beck-Sickinger, Annette G.
DOI：
10.1073/pnas.0813012106
发表时间：
2009-07-07
影响因子：
11.1
作者：
Fuller, Amelia A.;Du, Deguo;Kelly, Jeffery W.
通讯作者：
Kelly, Jeffery W.
影响因子：
3.7
作者：
Hartman, Matthew C. T.;Josephson, Kristopher;Szostak, Jack W.
通讯作者：
Szostak, Jack W.