Zhang Bin, Liu Ji-Feng, Xu Yingwu, Ng Shi-Chung
ArQule Biomedical Institute, ArQule Incorporated, 333 Providence Highway, Norwood, MA 02062, USA.
Biochem Biophys Res Commun. 2008 Aug 8;372(4):565-70. doi: 10.1016/j.bbrc.2008.05.074. Epub 2008 May 27.
HsEg5 is an important mitotic kinesin responsible for bipolar spindle formation at early mitosis. A rich body of evidence shows that inhibition of HsEg5 can result in mitotic arrest followed by cellular apoptosis. Recently identified HsEg5 inhibitor, CK0238273, exhibits potent antitumor activity and is currently in clinical trial. Here we report the cocrystal structure of the motor domain of HsEg5 in complex with CK0238273 at a 2.15 A resolution. Compared to the previously published HsEg5-Monastrol complex structure, CK0238273 shares the same induced-fit pocket with similar allosteric inhibitory mechanism. However, CK0238273 shows better fitting to the binding pocket with 65% increase of hydrophobic interaction area than that of Monastrol. Some unique hydrophilic interactions were also observed mostly between the phenyl ring and 8-chloro on quinazolinone of CK0238273 with ARG221 and GLY217. We believe that the combination of these interactions defines the superior potency and specificity of CK0238273.
HsEg5是一种重要的有丝分裂驱动蛋白，负责在有丝分裂早期形成双极纺锤体。大量证据表明，抑制HsEg5会导致有丝分裂停滞，随后细胞凋亡。最近鉴定出的HsEg5抑制剂CK0238273具有强大的抗肿瘤活性，目前正处于临床试验阶段。在此，我们报告了HsEg5运动结构域与CK0238273复合物的共晶体结构，分辨率为2.15埃。与先前发表的HsEg5-莫那可林复合物结构相比，CK0238273具有相同的诱导契合口袋，且变构抑制机制相似。然而，CK0238273与结合口袋的契合度更好，疏水相互作用面积比莫那可林增加了65%。还观察到一些独特的亲水相互作用，主要发生在CK0238273喹唑啉酮上的苯环和8-氯与ARG221和GLY217之间。我们认为，这些相互作用的组合决定了CK0238273的卓越效力和特异性。
