Structural and Thermodynamic Basis of the Enhanced Interaction between Kinesin Spindle Protein Eg5 and STLC-type Inhibitors
Structural and Thermodynamic Basis of the Enhanced Interaction between Kinesin Spindle Protein Eg5 and STLC-type Inhibitors
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DOI：
10.1021/acsomega.8b00778
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发表时间：
2018-09
期刊：
影响因子：
4.1
通讯作者：
H. Yokoyama;J. Sawada;Kohei Sato;N. Ogo;N. Kamei;Y. Ishikawa;K. Hara;A. Asai;H. Hashimoto
中科院分区：
文献类型：
--
作者：
H. Yokoyama;J. Sawada;Kohei Sato;N. Ogo;N. Kamei;Y. Ishikawa;K. Hara;A. Asai;H. Hashimoto
为了更好地理解蛋白质与抑制剂的相互作用，我们报告了 S-三苯甲基-L-半胱氨酸 (STLC) 衍生物与驱动蛋白纺锤体蛋白 Eg5 运动结构域之间相互作用的结构、热力学和生物学分析。 STLC 型抑制剂与 Eg5 的结合是焓驱动的，并且在熵上是不利的。在 STLC 的一个苯环中引入对甲氧基取代基增强了其抑制活性，这可能是由于形状互补性增加而导致更大的焓增益。取代基适合于结合袋中的凹槽。为了避免空间位阻，将取代的 STLC 推向与凹槽相反的一侧，这增强了 Eg5 与抑制剂其余部分的相互作用。在两个苯环之间进一步引入乙烯键可通过减少形成复合物时的熵损失来增强 Eg5 抑制活性。这项研究提供了在不形成额外氢键的情况下增强蛋白质与抑制剂相互作用的有价值的例子。
For a better understanding of protein–inhibitor interactions, we report structural, thermodynamic, and biological analyses of the interactions between S-trityl-l-cysteine (STLC) derivatives and the motor domain of kinesin spindle protein Eg5. Binding of STLC-type inhibitors to Eg5 was enthalpically driven and entropically unfavorable. The introduction of a para-methoxy substituent in one phenyl ring of STLC enhances its inhibitory activity resulting from a larger enthalpy gain possibly due to the increased shape complementarity. The substituent fits to a recess in the binding pocket. To avoid steric hindrance, the substituted STLC is nudged toward the side opposite to the recess, which enhances the interaction of Eg5 with the remaining part of the inhibitor. Further introduction of an ethylene linkage between two phenyl rings enhances Eg5 inhibitory activity by reducing the loss of entropy in forming the complex. This study provides valuable examples of enhancing protein–inhibitor interactions without forming additional hydrogen bonds.