Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5
Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5
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DOI：
10.1016/s1074-5521(02)00212-0
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发表时间：
2002-09-01
影响因子：
--
通讯作者：
Mitchison, TJ
中科院分区：
文献类型：
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作者：
Maliga, Z;Kapoor, TM;Mitchison, TJ
Monastrol是一种细胞渗透性的运动蛋白Eg5抑制剂，已被用来探测有丝分裂纺锤体的动态组织。monastrol抑制Eg5功能的机制尚不清楚。我们发现monastrol抑制Eg5运动区域的基础和微管刺激的atp酶活性。与许多ATP酶抑制剂不同，monastrol不与ATP结合Eg5竞争。Monastrol似乎抑制微管刺激的ADP从Eg5释放，但不与微管结合竞争，这表明Monastrol结合了运动域的一个新的变弹性位点。最后，我们确定(S)monastrol，与(R)-对映体相比，在体外和体内都是一种更有效的Eg5活性抑制剂。未来的结构研究应该有助于设计更有效的Eg5抑制剂，用于抗癌药物和细胞生物试剂。
Monastrol, a cell-permeable inhibitor of the kinesin Eg5, has been used to probe the dynamic organization of the mitotic spindle. The mechanism by which monastrol inhibits Eg5 function is unknown. We found that monastrol inhibits both the basal and the microtubule-stimulated ATPase activity of the Eg5 motor domain. Unlike many ATPase inhibitors, monastrol does not compete with ATP binding to Eg5. Monastrol appears to inhibit microtubule-stimulated ADP release from Eg5 but does not compete with microtubule binding, suggesting that monastrol binds a novel allosteric site in the motor domain. Finally, we established that (S)monastrol, as compared to the (R)-enantiomer, is a more potent inhibitor of Eg5 activity in vitro and in vivo. Future structural studies should help in designing more potent Eg5 inhibitors for possible use as anticancer drugs and cell biological reagents.