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Small-molecule and mutational analysis of allosteric Eg5 inhibition by monastrol

机译：Monastrol抑制变构Eg5的小分子和突变分析

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Background A recent crystal structure of monastrol in a ternary complex with the kinesin Eg5 motor domain highlights a novel,induced-fit drug binding site at atomic resolution. Mutational obliteration of the monastrol binding site results in a monastrol-resistant, but otherwise catalytically active Eg5 motor domain.However,considering the conformational changes at this site,it is unclear what specific interactions stabilize the interaction between monastrol and the Eg5 motor domain. Results To study the molecular complementarity of the monastrol-Eg5 interaction,we used a combination of synthetic chemistry and targeted mutations in Eg5 to measure the contribution of specific contacts to inhibition of Eg5 in vitro and in cultured cells. Structure-activity data on chemical derivatives,sequence analysis of Eg5 homologs from different species,and the effect of mutations near the drug binding site were consistent with the crystal structure. Conclusions The mechanism of monastrol revealed by our data rationalizes its specificity for Eg5 over other kinesins and highlights a potential mechanism of drug resistance for anti- cancer therapy targeting this site in Eg5.
机译：背景技术与驱动蛋白Eg5马达结构域的三元复合物中的monastrol的最新晶体结构以原子分辨率突出了一个新颖的诱导拟合药物结合位点。 Monastrol结合位点的突变消除会产生Monastrol耐药性，但具有催化活性的Eg5运动域。但是，考虑到该位点的构象变化，目前尚不清楚什么特异性相互作用能稳定Monastrol与Eg5运动域之间的相互作用。结果为了研究monastrol-Eg5相互作用的分子互补性，我们使用合成化学方法和Eg5中的靶向突变相结合，测量了特定接触对体外和培养细胞对Eg5抑制的贡献。化学衍生物的结构活性数据，不同物种的Eg5同源物序列分析以及药物结合位点附近的突变影响与晶体结构一致。结论我们的数据揭示了monastrol的机制合理化了其对Eg5相对于其他驱动蛋白的特异性，并突出了针对Eg5上该位点的抗癌治疗的潜在耐药性机制。

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