An evolutionary trace method defines binding surfaces common to protein families
An evolutionary trace method defines binding surfaces common to protein families
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DOI：
10.1006/jmbi.1996.0167
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发表时间：
1996-03-29
影响因子：
5.6
通讯作者：
Cohen, FE
中科院分区：
文献类型：
--
作者：
Lichtarge, O;Bourne, HR;Cohen, FE
蛋白质的X-射线或核磁共振结构通常是在没有配体的情况下得到的，即使当完整的络合物的结构可用时，在功能和能量上有意义的接触区域可能是由配体之间的空间接近而推导出的几何界面的一个特殊子集。因此，即使在解决了一个结构之后，定位蛋白质功能界面并了解其组成残基的作用仍然是一个主要的理论和实验目标。进化踪迹方法是一种系统、透明和新颖的预测技术，用于识别已知结构的蛋白质中的活性位点和功能界面。它的基础是从同源蛋白质的序列保守模式中提取功能重要的残基，并将它们映射到蛋白质表面以生成识别功能界面的簇。核激素受体的SH2和SH3模块化信号域和DNA结合域为我们方法的准确性和有效性提供了测试。在每种情况下，进化轨迹描绘出功能表位并识别对结合特异性至关重要的残基。基于突变进化分析和蛋白质家族的结构同源性，这种简单而通用的方法应该有助于将重点放在大分子结构-功能关系的定点突变研究以及分子识别的特异性研究上。更广泛地说，它为判断蛋白质结构中每个残基的功能或结构作用提供了一个进化的视角。(C)1996年学术出版社有限公司
X-ray or NMR structures of proteins are often derived without their ligands, and even when the structure of a full complex is available, the area of contact that is functionally and energetically significant may be a specialized subset of the geometric interface deduced from the spatial proximity between ligands. Thus, even after a structure is solved, it remains a major theoretical and experimental goal to localize protein functional interfaces and understand the role of their constituent residues. The evolutionary trace method is a systematic, transparent and novel predictive technique that identifies active sites and functional interfaces in proteins with known structure. It is based on the extraction of functionally important residues from sequence conservation patterns in homologous proteins, and on their mapping onto the protein surface to generate clusters identifying functional interfaces. The SH2 and SH3 modular signaling domains and the DNA binding domain of the nuclear hormone receptors provide tests for the accuracy and validity of our method. In each case, the evolutionary trace delineates the functional epitope and identifies residues critical to binding specificity. Based on mutational evolutionary analysis and on the structural homology of protein families, this simple and versatile approach should help focus site-directed mutagenesis studies of structure-function relationships in macromolecules, as well as studies of specificity in molecular recognition. More generally, it provides an evolutionary perspective for judging the functional or structural role of each residue in a protein structure. (C) 1996 Academic Press Limited