The importance of being tyrosine: lessons in molecular recognition from minimalist synthetic binding proteins.
The importance of being tyrosine: lessons in molecular recognition from minimalist synthetic binding proteins.
复制标题
DOI：
10.1021/cb800314v
复制
发表时间：
2009-05-15
影响因子：
4
通讯作者：
Sidhu, Sachdev S.
中科院分区：
文献类型：
--
作者：
Koide, Shohei;Sidhu, Sachdev S.
用严格限制的化学多样性构建的组合文库已经产生了高功能的合成结合蛋白。这些最低限度的结合位点的结构分析揭示了介导分子接触的大酪氨酸残基和提供空间和灵活性的小丝氨酸/甘氨酸残基的主导作用。使用有限的残基类型来构建优化的结合蛋白的概念反映了小分子药物开发领域中的发现，其中已经提出大多数药物是从由不同框架呈现的有限的一组侧链构建的。酪氨酸的物理化学性质使其成为介导分子识别最有效的氨基酸，蛋白质工程师利用这些特性构建富含酪氨酸的蛋白质结合位点，其在亲和力和特异性方面优于天然蛋白质。来自先前研究的知识可以用于改进当前的设计，因此，合成蛋白质文库将继续发展和改进。在不久的将来，合成的结合蛋白似乎将取代天然抗体用于大多数目的，而且，合成蛋白将使许多新的应用超出天然蛋白的范围。
Combinatorial libraries built with severely restricted chemical diversity have yielded highly functional synthetic binding proteins. Structural analyses of these minimalist binding sites have revealed the dominant role of large tyrosine residues for mediating molecular contacts and of small serine/glycine residues for providing space and flexibility. The concept of using limited residue types to construct optimized binding proteins mirrors findings in the field of small molecule drug development, where it has been proposed that most drugs are built from a limited set of side chains presented by diverse frameworks. The physicochemical properties of tyrosine make it the amino acid that is most effective for mediating molecular recognition, and protein engineers have taken advantage of these characteristics to build tyrosine-rich protein binding sites that outperform natural proteins in terms of affinity and specificity. Knowledge from preceding studies can be used to improve current designs, and thus, synthetic protein libraries will continue to evolve and improve. In the near future, it seems likely that synthetic binding proteins will supersede natural antibodies for most purposes, and moreover, synthetic proteins will enable many new applications beyond the scope of natural proteins.
登录
查看更多内容
DOI：
10.1073/pnas.0812952106
发表时间：
2009-03-03
影响因子：
11.1
作者：
Gao, Junjun;Sidhu, Sachdev S.;Wells, James A.
通讯作者：
Wells, James A.
影响因子：
5.6
作者：
Gilbreth, Ryan N.;Esaki, Kaori;Koide, Shohei
通讯作者：
Koide, Shohei
影响因子：
5.6
作者：
Birtalan, Sara;Zhang, Yingnan;Sidhu, Sachdev S.
通讯作者：
Sidhu, Sachdev S.
影响因子：
5.6
作者：
Jespers, L;Schon, O;Winter, G
通讯作者：
Winter, G
影响因子：
4.8
作者：
Kawe, Martin;Forrer, Patrik;Plueckthun, Andreas
通讯作者：
Plueckthun, Andreas