Yokoyama Hideshi, Sawada Jun-ichi, Katoh Shiori, Matsuno Kenji, Ogo Naohisa, Ishikawa Yoshinobu, Hashimoto Hiroshi, Fujii Satoshi, Asai Akira
†Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
‡Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
ACS Chem Biol. 2015 Apr 17;10(4):1128-36. doi: 10.1021/cb500939x. Epub 2015 Feb 3.
Kinesin spindle protein Eg5 is a target for anticancer therapies, and small molecule inhibitors of its ATPase activity have been developed. We herein report for the first time the crystal structure of and biochemical studies on the Eg5 motor domain in complex with a new type of allosteric inhibitor. The biphenyl-type inhibitor PVZB1194 binds to the α4/α6 allosteric pocket 15 Å from the ATP-binding pocket, which differs from conventional allosteric inhibitors that bind to the allosteric L5/α2/α3 pocket of Eg5. Binding of the inhibitor is involved in the neck-linker conformation and also causes conformational changes around the ATP-binding pocket through Tyr104 to affect the interaction of ATP with the pocket. This structure provides useful information for the development of novel types of allosteric drugs as well as a novel insight into the molecular mechanism responsible for regulating the motor activity of kinesins.
驱动蛋白纺锤体蛋白Eg5是抗癌治疗的一个靶点，并且已经开发出了其ATP酶活性的小分子抑制剂。我们在此首次报道了与一种新型变构抑制剂结合的Eg5运动结构域的晶体结构及生化研究。联苯型抑制剂PVZB1194结合到距离ATP结合口袋15 Å的α4/α6变构口袋，这与结合到Eg5变构L5/α2/α3口袋的传统变构抑制剂不同。抑制剂的结合涉及颈部连接体构象，并且还通过Tyr104引起ATP结合口袋周围的构象变化，从而影响ATP与该口袋的相互作用。该结构为新型变构药物的开发提供了有用信息，也为负责调节驱动蛋白运动活性的分子机制提供了新的见解。
