Biomedicinal Information Research Center (BIRC) and Molecular Profiling Research Center (Molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-3-26 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
Japan Biological Informatics Consortium (JBIC), 2-3-26 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
Angew Chem Int Ed Engl. 2016 Nov 14;55(47):14606-14609. doi: 10.1002/anie.201607474. Epub 2016 Oct 20.
The thermodynamic properties of a ligand in the bound state affect its binding specificity. Strict binding specificity can be achieved by introducing multiple spatially defined interactions, such as hydrogen bonds and van der Waals interactions, into the ligand-receptor interface. These introduced interactions are characterized by restricted local dynamics and improved surface complementarity in the bound state. In this study, we experimentally evaluated the local dynamics and the surface complementarity of weak-affinity ligands in the receptor-bound state by forbidden coherence transfer analysis in free-bound exchange systems (Ex-FCT), using the interaction between a ligand, a myocyte-enhancer factor 2A (MEF2A) docking peptide, and a receptor, p38α, as a model system. The Ex-FCT analyses successfully provided information for the rational design of a ligand with higher affinity and preferable thermodynamic properties for p38α.
配体在结合状态下的热力学性质会影响其结合特异性。通过在配体-受体界面中引入多个空间定义的相互作用，如氢键和范德华相互作用，可以实现严格的结合特异性。这些引入的相互作用的特点是在结合状态下局部动力学受限和表面互补性提高。在这项研究中，我们通过使用肌细胞增强因子 2A (MEF2A) 对接肽与受体 p38α 之间的相互作用作为模型系统，通过游离-结合交换体系（Ex-FCT）中的禁止相干转移分析（Forbidden coherence transfer analysis，Ex-FCT），实验评估了弱亲和力配体在受体结合状态下的局部动力学和表面互补性。Ex-FCT 分析成功地为具有更高亲和力和更优热力学性质的 p38α 配体的合理设计提供了信息。
