Schieborr Ulrich, Vogtherr Martin, Elshorst Bettina, Betz Marco, Grimme Susanne, Pescatore Barbara, Langer Thomas, Saxena Krishna, Schwalbe Harald
Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe Universität Frankfurt, Marie Curie Strasse 11, 60439 Frankfurt am Main, Germany.
Chembiochem. 2005 Oct;6(10):1891-8. doi: 10.1002/cbic.200500092.
Here we present an NMR-based approach to solving protein-ligand structures. The procedure is guided by biophysical, biochemical, or knowledge-based data. The structures are mainly derived from ligand-induced chemical-shift perturbations (CSP) induced in the resonances of the protein and ligand-detected saturated transfer difference signals between ligands and selectively labeled proteins (SOS-NMR). Accuracy, as judged by comparison with X-ray results, depends on the nature and completeness of the experimental data. An experimental protocol is proposed that starts with calculations that make use of readily available chemical-shift perturbations as experimental constraints. If necessary, more sophisticated experimental results have to be added to improve the accuracy of the protein-ligand complex structure. The criteria for evaluation and selection of meaningful complex structures are discussed. These are exemplified for three complexes, and we show that the approach bridges the gap between theoretical docking approaches and complex NMR schemes for determining protein-ligand complexes; especially for relatively weak binders that do not lead to intermolecular NOEs.
在此，我们展示了一种基于核磁共振（NMR）的解析蛋白质-配体结构的方法。该过程由生物物理、生化或基于知识的数据引导。结构主要源自蛋白质共振中由配体诱导的化学位移扰动（CSP）以及配体与选择性标记蛋白质之间的配体检测饱和转移差异信号（SOS-NMR）。通过与X射线结果比较判断，准确性取决于实验数据的性质和完整性。提出了一种实验方案，该方案始于利用易于获得的化学位移扰动作为实验约束的计算。如有必要，必须添加更复杂的实验结果以提高蛋白质-配体复合物结构的准确性。讨论了评估和选择有意义的复合物结构的标准。以三种复合物为例进行说明，并且我们表明该方法弥合了理论对接方法与用于确定蛋白质-配体复合物的复杂NMR方案之间的差距；特别是对于不会导致分子间核Overhauser效应（NOE）的相对较弱的结合剂。
