Structural and Thermodynamic Basis of the Enhanced Interactionbetween Kinesin Spindle Protein Eg5 and STLC-type Inhibitors

摘要

For a better understanding of protein?inhibitor interactions, wereport structural, thermodynamic, and biological analyses of the interactionsbetween S-trityl-L-cysteine (STLC) derivatives and the motor domain of kinesinspindle protein Eg5. Binding of STLC-type inhibitors to Eg5 was enthalpicallydriven and entropically unfavorable. The introduction of a para-methoxysubstituent in one phenyl ring of STLC enhances its inhibitory activity resultingfrom 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, whichenhances the interaction of Eg5 with the remaining part of the inhibitor. Furtherintroduction of an ethylene linkage between two phenyl rings enhances Eg5inhibitory activity by reducing the loss of entropy in forming the complex. Thisstudy provides valuable examples of enhancing protein?inhibitor interactionswithout forming additional hydrogen bonds.