Department of Chemistry, New York University, New York, NY 10003, USA.
Department of Chemistry, New York University, New York, NY 10003, USA.
Curr Opin Chem Biol. 2018 Jun;44:16-22. doi: 10.1016/j.cbpa.2018.05.013. Epub 2018 May 24.
Rationally designed protein-protein interaction inhibitors mimic interfacial binding epitopes, specifically residues that contribute significantly to binding. However, direct mimicry often does not lead to high affinity ligands because the natural complexes themselves are functionally transient and of low affinity. The mimics typically need to be optimized for potency. Engineered proteins displaying conformationally-defined epitopes may serve as attractive alternatives to natural protein partners as they can be strictly screened for tight binding. The advantage of focused screens with conformationally-defined protein scaffolds is that conservation of the geometry of the natural binding epitopes may preserve binding site specificity while allowing direct mimicry by various synthetic secondary structure scaffolds. Here we review different classes of engineered proteins for their binding epitope geometry and as leads for synthetic secondary and tertiary structure mimics.
理性设计的蛋白质-蛋白质相互作用抑制剂模拟界面结合表位，特别是对结合有重要贡献的残基。然而，由于天然复合物本身具有功能瞬态和低亲和力，直接模拟通常不会导致高亲和力配体。模拟物通常需要优化效力。展示构象定义表位的工程蛋白可以作为天然蛋白配体的有吸引力的替代品，因为它们可以严格筛选紧密结合。使用构象定义的蛋白质支架进行有针对性筛选的优势在于，天然结合表位的几何形状的保守性可以保持结合位点特异性，同时允许各种合成二级结构支架进行直接模拟。在这里，我们回顾了不同类型的工程蛋白的结合表位几何形状及其作为合成二级和三级结构模拟物的先导。
