Comprehensive and quantitative mapping of energy landscapes for protein-protein interactions by rapid combinatorial scanning
Comprehensive and quantitative mapping of energy landscapes for protein-protein interactions by rapid combinatorial scanning
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DOI：
10.1074/jbc.m603826200
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发表时间：
2006-08-04
影响因子：
4.8
通讯作者：
Sidhu, Sachdev S.
中科院分区：
文献类型：
--
作者：
Pal, Gabor;Kouadio, Jean-Louis K.;Sidhu, Sachdev S.
开发了一种新颖的定量饱和（QS）扫描策略，以获得跨大型蛋白质-蛋白质界面的所有可能突变的结构和功能影响的综合数据库。 QS 扫描方法应用于人生长激素 (hGH) 与其受体 (hGHR) 结合的高亲和力位点。尽管已发表的描述该系统的结构功能数据库可能是任何大型蛋白质-蛋白质界面中最广泛的，但它仍然太稀疏，无法准确描述控制相互作用的能量学的性质。我们的综合数据库提供了结合位点的完整视图，并为蛋白质-蛋白质相互作用的一般原理提供了重要的新见解。 hGH 结合界面对突变具有高度适应性，但耐受突变的性质挑战了人们普遍接受的关于控制蛋白质-蛋白质相互作用的进化和生物物理压力的观点。许多被认为化学保守的取代是不被容忍的，而相反，许多非保守取代是可以接受的。此外，跨物种的保守性不能很好地预测界面上耐受取代的化学特征。与普遍接受的期望的许多偏差表明，突变耐受性高度依赖于环境，而且，无法通过我们当前的知识库进行预测。综合QS扫描产生的数据类型可以填补结构-功能矩阵中的空白。来自其他蛋白质-蛋白质相互作用研究的类似数据库的汇编应该极大地有助于解释和设计分子识别的计算方法的发展。
A novel, quantitative saturation (QS) scanning strategy was developed to obtain a comprehensive data base of the structural and functional effects of all possible mutations across a large protein-protein interface. The QS scan approach was applied to the high affinity site of human growth hormone (hGH) for binding to its receptor (hGHR). Although the published structure-function data base describing this system is probably the most extensive for any large protein-protein interface, it is nonetheless too sparse to accurately describe the nature of the energetics governing the interaction. Our comprehensive data base affords a complete view of the binding site and provides important new insights into the general principles underlying protein-protein interactions. The hGH binding interface is highly adaptable to mutations, but the nature of the tolerated mutations challenges generally accepted views about the evolutionary and biophysical pressures governing protein-protein interactions. Many substitutions that would be considered chemically conservative are not tolerated, while conversely, many non-conservative substitutions can be accommodated. Furthermore, conservation across species is a poor predictor of the chemical character of tolerated substitutions across the interface. Numerous deviations from generally accepted expectations indicate that mutational tolerance is highly context dependent and, furthermore, cannot be predicted by our current knowledge base. The type of data produced by the comprehensive QS scan can fill the gaps in the structure-function matrix. The compilation of analogous data bases from studies of other protein-protein interactions should greatly aid the development of computational methods for explaining and designing molecular recognition.