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.

中文翻译：

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突如其来的策略：扩大化学遗传学的范围

人类基因组的成功作图引发了人们对解密基因序列中编码的功能信息的广泛兴趣。但是，由于蛋白质超家族成员之间序列的高度保守性以及拓扑和生化相似性，揭示特定蛋白质的生理作用一直是一项艰巨的任务。化学遗传方法对理解蛋白质功能做出了重大贡献。一项被称为“撞孔法”的研究已令人信服地证明，在蛋白质-小分子界面处进行工程改造是阐明特定基因产物功能的有力方法。通过以互补方式操纵蛋白质-配体相互作用的空间成分，开发了一个正交系统来探测特定的酶-辅因子对，而不会受到相关成员的干扰。本文概述了当前为扩展用于多种蛋白质类别及其应用的方法所做的努力。还强调了解决当代生物学问题的潜在未来创新。