Structure and assembly of designed β-hairpin peptides in crystals as models for β-sheet aggregation
Structure and assembly of designed β-hairpin peptides in crystals as models for β-sheet aggregation
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DOI：
10.1021/bi035522g
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发表时间：
2004-02-24
期刊：
影响因子：
2.9
通讯作者：
Balaram, P
中科院分区：
文献类型：
--
作者：
Aravinda, S;Harini, VV;Balaram, P
从头设计的β-发夹肽通常不容易结晶。描述了四种合成肽β-发夹的晶体结构：Boc-Leu-Val-Val-DPro-Gly-Leu-Phe-Val-OMe（1）、Boc-Leu-Phe-Val-DPro-Ala-Leu-Phe-Val-OMe（2）、Boc-Leu-Val-Val-DPro-Aib-Leu-Val-Val-OMe（3）和Boc-Met-Leu-Phe-Val-DPro-Ala-Leu-Val-Val-Phe-OMe（4）。位于中心的DPro-Xxx片段促进主要β-转角形成，从而使β-发夹结构成核。在所有四种肽中，通过中心II型DPro-Xxx β-转角成核的明确的β-发夹已经通过X射线衍射表征，提供了八种晶体学独立的发夹的视图。在肽1-3中，三个分子内交叉链氢键稳定了观察到的β-发夹，在末端有一些磨损的结构。在肽4中，四个分子内交叉链氢键稳定发夹。肽1-4揭示了β-发夹堆积成晶体的共同特征。由相邻分子的反平行链之间形成的分子间氢键介导的二维片层形成是一个反复出现的主题。二维片材到晶体中的填充在第三维中通过桥接溶剂和突出侧链的相互作用来介导，所述突出侧链在片材的任一面上取向。在所有情况下，观察到中心DPro-Xxx肽单元β-转角的溶剂化。与更平坦的肽4中的较大发夹相比，八肽中形成的发夹明显弯曲。晶体结构提供了对规则晶体阵列中β-切片包装的可能模式的见解，这可能为理解淀粉样蛋白原纤维中的β-三明治和交叉β-结构提供起点。
De novo designed beta-hairpin peptides have generally been recalcitrant to crystallization. The crystal structures of four synthetic peptide beta-hairpins, Boc-Leu-Val-Val-DPro-Gly-Leu-Phe-Val-OMe (1), Boc-Leu-Phe-Val-DPro-Ala-Leu-Phe-Val-OMe (2), Boc-Leu-Val-Val-DPro-Aib-Leu-Val-Val-OMe (3), and Boc-Met-Leu-Phe-Val-DPro-Ala-Leu-Val-Val-Phe-OMe (4), are described. The centrally positioned DPro-Xxx segment promotes prime beta-turn formation, thereby nucleating beta-hairpin structures. In all four peptides well-defined beta-hairpins nucleated by central type II' DPro-Xxx beta-turns have been characterized by X-ray diffraction, providing a view of eight crystallographically independent hairpins. In peptides 1-3 three intramolecular cross-strand hydrogen bonds stabilized the observed beta-hairpin, with some fraying of the structures at the termini. In peptide 4, four intramolecular cross-strand hydrogen bonds stabilized the hairpin. Peptides 1-4 reveal common features of packing of beta-hairpins into crystals. Two-dimensional sheet formation mediated by intermolecular hydrogen bonds formed between antiparallel strands of adjacent molecule is a recurrent theme. The packing of two-dimensional sheets into the crystals is mediated in the third dimension by bridging solvents and interactions of projecting side chains, which are oriented on either face of the sheet. In all cases, solvation of the central DPro-Xxx peptide unit beta-turn is observed. The hairpins formed in the octapeptides are significantly buckled as compared to the larger hairpin in peptide 4, which is much flatter. The crystal structures provide insights into the possible modes of beta-shect packing in regular crystalline arrays, which may provide a starting point for understanding beta-sandwich and cross-beta-structures in amyloid fibrils.