Amino Acids, Peptides and Proteins - Volume 39
Amino Acids, Peptides and Proteins - Volume 39
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氨基酸、肽和蛋白质 - 第 39 卷
DOI：
10.1039/9781849739962-00148
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Oheix E
中科院分区：
文献类型：
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作者：
Oheix E
蛋白质二级结构主要通过骨架相互作用来稳定。然而，较弱的相互作用，特别是侧链相互作用，在某些情况下，可以触发折叠事件或形成更高级的结构。互补测序和结构研究已经允许鉴定与二级、三级甚至四级结构有关的一些序列-结构关系。令人惊讶的是，天然蛋白质序列很少最大化这些相互作用，部分原因是随机进化因子，因此天然支架通常很大，以实现足够的稳定性。从第一原理或从头设计良好折叠的肽，首先旨在制备具有最佳稳定性和较短序列长度的肽支架。虽然在20世纪90年代在这一领域取得了重大进展，但最近在这些支架中引入金属离子辅因子取得了重要进展。已知金属离子对大约三分之一的蛋白质的正确功能是必不可少的，其作用包括催化、电子转移、稳定以及小分子的结合和运输。1因此，人们对挑战我们对金属蛋白活性的理解很感兴趣。这可以通过修饰（诱变）、交换（易位）或从头设计（从头设计）引入金属离子活性位点的肽基质来实现。与本报告相关的后一种策略提供了对金属离子及其肽支架之间相互依赖性的深入了解。实际上，金属离子配位偏好可用于指导肽组装，或者肽支架可用于在金属离子上强制实施不寻常的配位几何形状。除了配体的数量、性质和空间定位之外，金属离子化学可以通过调节第二配位球性质来调节。这种微妙的设计特征允许功能金属蛋白的配位球被有效地复制，反过来，它们的活动被模仿。重要的是，保留与天然蛋白质相同的支架（肽折叠、寡聚化状态等）。已经证明对于实现类似于本机的功能不是必需的。
Protein secondary structure is mainly stabilised by backbone interactions. However, weaker interactions, notably side-chain interactions, can, in some cases, trigger folding events or the formation of higher order structures. Complementary sequencing and structural studies have allowed some of the sequence-structure relationships pertaining to secondary, tertiary and even quaternary structures, to be identified. Surprisingly, natural protein sequences rarely maximise these interactions, partly due to the random evolution factor, thus natural scaffolds are often large in order to achieve sufficient stability. The design of well folded peptides from first-principles, or de novo, first aimed to prepare peptide scaffolds with optimum stability and shorter sequence lengths. Though significant progress in this area was reported in the 1990’s, recently important progress has been made introducing metal-ion co-factors into these scaffolds.Metal-ions are known to be essential for the correct function of around a third of all proteins with roles in catalysis, electron-transfer, stabilisation, as well as the binding and transport of small molecules. 1 Therefore there is great interest in challenging our understanding of metalloprotein activity. This can be achieved by either modifying (mutagenesis), exchanging (translocation), or designing from scratch (de novo design) the peptide matrix into which the metal-ion active site is introduced. The latter strategy, relevant to this report, provides insight into the interdependence between metal-ions and their peptide scaffolds. Indeed, metal-ion coordination preferences can be used to direct peptide assembly, or alternatively the peptide scaffold can be used to enforce an unusual coordination geometry on the metal-ion. In addition to the number, nature and spatial positioning of ligands, the metal-ion chemistry can be modulated by tuning the second coordination sphere properties. Such subtle design features allows the coordination spheres of functional metalloproteins to be effectively reproduced, and in turn, their activities mimicked. Importantly, retaining the same scaffold as the native protein (peptide fold, oligomerisation state etc.) has been shown to not be essential for achieving native-like functionality.