Koide Shohei, Sidhu Sachdev S
Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
ACS Chem Biol. 2009 May 15;4(5):325-34. doi: 10.1021/cb800314v.
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.
构建具有严格受限化学多样性的组合文库已产生了具有高度功能的合成结合蛋白。对这些简约结合位点的结构分析揭示了大酪氨酸残基在介导分子接触中的主导作用以及小丝氨酸/甘氨酸残基在提供空间和灵活性方面的主导作用。使用有限残基类型构建优化结合蛋白的概念反映了小分子药物开发领域的研究结果，在该领域有人提出，大多数药物是由不同框架呈现的有限侧链集合构建而成的。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了富含酪氨酸的蛋白质结合位点，这些位点在亲和力和特异性方面优于天然蛋白质。先前研究的知识可用于改进当前设计，因此合成蛋白文库将不断发展和完善。在不久的将来，合成结合蛋白似乎很可能在大多数用途上取代天然抗体，此外，合成蛋白将实现许多超出天然蛋白范围的新应用。
