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首页> 外文期刊>Biochemistry >High-resolution X-ray structure of the unexpectedly stable dimer of the (Lys(-2)-Arg(-1)-des(17-21))endothelin-1 peptide.
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High-resolution X-ray structure of the unexpectedly stable dimer of the (Lys(-2)-Arg(-1)-des(17-21))endothelin-1 peptide.

机译：高分辨率X射线结构的（Lys（-2）-Arg（-1）-des（17-21））内皮素-1肽的意外稳定的二聚体。

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摘要

Previous structural studies on the [Lys((-2))-Arg((-1))]endothelin-1 peptide (KR-ET-1), 540-fold less potent than ET-1, strongly suggested the presence of an intramolecular Arg(-1)-Asp(8) (R(-1)-D(8)) salt bridge that was also observed in the shorter [Lys((-2))-Arg((-1))-des(17-21)]endothelin-1 derivative (KR-CSH-ET). In addition, for these two analogues, we have shown that the Lys-Arg dipeptide, which belongs to the prosequence, significantly improves the formation of the native disulfide bonds (>or=96% instead of approximately 70% for ET-1). In contrast to what was inferred from NMR data, molecular dynamics simulations suggested that such an intramolecular salt bridge would be unstable. The KR-CSH-ET peptide has now been crystallized at pH 5.0 and its high-resolution structure determined ab initio at 1.13 A using direct methods. Unexpectedly, KR-CSH-ET was shown to be a head-to-tail symmetric dimer, and the overall interface involves two intermolecular R(-1)-D(8) salt bridges, a two-stranded antiparallel beta-sheet, and hydrophobic contacts. Molecular dynamics simulations carried out on this dimer clearly showed that the two intermolecular salt bridges were in this case very stable. Sedimentation equilibrium experiments unambiguously confirmed that KR-ET-1 and KR-CSH-ET also exist as dimers in solution at pH 5.0. On the basis of the new dimeric structure, previous NMR data were reinterpreted. Structure calculations were performed using 484 intramolecular and 38 intermolecular NMR-derived constraints. The solution and the X-ray structures of the dimer are very similar (mean rmsd of 0.85 A). Since the KR dipeptide at the N-terminus of KR-CSH-ET is present in the prosequence, it can be hypothesized that similar intermolecular salt bridges could be involved in the in vivo formation of the native disulfide bonds of ET-1. Therefore, it appears to be likely that the prosequence does assist the ET-1 folding in a chaperone-like manner before successive cleavages that yield the bioactive ET-1 hormone.
机译：先前对[Lys（（-2））-Arg（（-1））]内皮素1肽（KR-ET-1）的结构研究，其效力比ET-1低540倍，强烈表明存在分子内Arg（-1）-Asp（8）（R（-1）-D（8））盐桥，在较短的[Lys（（-2））-Arg（（-1））-des中也观察到（17-21）]内皮素-1衍生物（KR-CSH-ET）。此外，对于这两个类似物，我们已经证明属于该序列的Lys-Arg二肽显着改善了天然二硫键的形成（>或= 96％，而不是ET-1的约70％）。与从NMR数据推断的相反，分子动力学模拟表明这种分子内盐桥是不稳定的。现在，KR-CSH-ET肽已在pH 5.0下结晶，并使用直接方法从头开始在1.13 A下确定了其高分辨率结构。出乎意料的是，KR-CSH-ET被证明是头对尾对称的二聚体，整个界面包括两个分子间R（-1）-D（8）盐桥，一个两链反平行β-折叠和疏水接触。在此二聚体上进行的分子动力学模拟清楚地表明，在这种情况下，两个分子间盐桥非常稳定。沉淀平衡实验明确证实，KR-ET-1和KR-CSH-ET在pH 5.0的溶液中也以二聚体形式存在。在新的二聚体结构的基础上，重新解释了以前的NMR数据。使用484个分子内和38个分子间NMR衍生的约束条件进行结构计算。二聚体的溶液和X射线结构非常相似（均方根值为0.85 A）。由于前者存在于KR-CSH-ET N端的KR二肽，因此可以假设类似的分子间盐桥可能参与了ET-1天然二硫键的体内形成。因此，在产生生物活性的ET-1激素的连续裂解之前，前序似乎有可能以伴侣状方式辅助ET-1的折叠。

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