A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
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DOI：
10.1038/nchembio.1629
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发表时间：
2014-10
影响因子：
14.8
通讯作者：
Knapp S
中科院分区：
文献类型：
--
作者：
Chaikuad A;Tacconi EM;Zimmer J;Liang Y;Gray NS;Tarsounas M;Knapp S
ERK通路的激活是癌症的标志，针对上游信号伙伴的靶向导致了批准的药物的开发。最近，SCH772984被证明是一种选择性的、有效的ERK1/2抑制剂。在此，我们报道了其显著选择性的结构机理。在ERK1/2中，SCH772984诱导了一个迄今未知的结合口袋，该口袋容纳了哌嗪-苯基-嘧啶装饰。这种新的结合口袋是通过磷酸结合环的非活性构象和螺旋αC的向外倾斜而产生的。相比之下，SCH772984与靶外haspin和JNK1的结构测定揭示了典型的但两种截然不同的I型结合模式。有趣的是，与ERK1/2的新结合模式在体外和基于细胞的检测系统中与缓慢的结合动力学有关。所描述的SCH772984与ERK1/2的结合模式使设计一种具有长时间靶向活性的新型特异性激酶抑制剂成为可能。
Activation of the ERK pathway is a hallmark of cancer and targeting of upstream signalling partners led to the development of approved drugs. Recently SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induced a so far unknown binding pocket that accommodated the piperazine-phenyl-pyrimidine decoration. This novel binding pocket was created by an inactive conformation of the phosphate binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed canonical but two distinct type-I binding modes. Intriguingly, the novel binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.