Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Cell Chem Biol. 2018 Oct 18;25(10):1171-1184. doi: 10.1016/j.chembiol.2018.07.001. Epub 2018 Aug 2.
Successful mapping of the human genome has sparked a widespread interest in deciphering functional information encoded in gene sequences. However, because of the high degree of conservation in sequences along with topological and biochemical similarities among members of a protein superfamily, uncovering physiological role of a particular protein has been a challenging task. Chemical genetic approaches have made significant contributions toward understanding protein function. One such effort, dubbed the bump-and-hole approach, has convincingly demonstrated that engineering at the protein-small molecule interface constitutes a powerful method for elucidating the function of a specific gene product. By manipulating the steric component of protein-ligand interactions in a complementary manner, an orthogonal system is developed to probe a specific enzyme-cofactor pair without interference from related members. This article outlines current efforts to expand the approach for diverse protein classes and their applications. Potential future innovations to address contemporary biological problems are highlighted as well.
成功绘制人类基因组图谱引发了人们广泛关注，以期破译基因序列中所编码的功能信息。然而，由于序列的高度保守性，以及蛋白质超家族成员之间的拓扑和生化相似性，揭示特定蛋白质的生理功能一直是一项具有挑战性的任务。化学遗传学方法在理解蛋白质功能方面做出了重大贡献。其中一种方法，称为“凸凹法”，令人信服地证明了在蛋白质-小分子界面上进行工程设计是阐明特定基因产物功能的一种有力方法。通过以互补的方式操纵蛋白质-配体相互作用的空间位阻成分，开发出一种正交系统，可在不受相关成员干扰的情况下探测特定的酶-辅酶对。本文概述了当前为不同蛋白质类别的努力和它们的应用。还强调了潜在的未来创新，以解决当代生物学问题。
