Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.
Int J Mol Sci. 2020 Oct 26;21(21):7953. doi: 10.3390/ijms21217953.
Extracellular signal-regulated kinase 3 (ERK3), known also as mitogen-activated protein kinase 6 (MAPK6), is an atypical member of MAPK kinase family, which has been poorly studied. Little is known regarding its function in biological processes, yet this atypical kinase has been suggested to play important roles in the migration and invasiveness of certain cancers. The lack of tools, such as a selective inhibitor, hampers the study of ERK3 biology. Here, we report the crystal structure of the kinase domain of this atypical MAPK kinase, providing molecular insights into its distinct ATP binding pocket compared to the classical MAPK ERK2, explaining differences in their inhibitor binding properties. Medium-scale small molecule screening identified a number of inhibitors, several of which unexpectedly exhibited remarkably high inhibitory potencies. The crystal structure of CLK1 in complex with CAF052, one of the most potent inhibitors identified for ERK3, revealed typical type-I binding mode of the inhibitor, which by structural comparison could likely be maintained in ERK3. Together with the presented structural insights, these diverse chemical scaffolds displaying both reversible and irreversible modes of action, will serve as a starting point for the development of selective inhibitors for ERK3, which will be beneficial for elucidating the important functions of this understudied kinase.
细胞外信号调节激酶 3（ERK3），也称为丝裂原活化蛋白激酶 6（MAPK6），是丝裂原活化蛋白激酶激酶家族中的一个非典型成员，其研究甚少。尽管人们对其在生物学过程中的功能知之甚少，但这种非典型激酶已被认为在某些癌症的迁移和侵袭中发挥重要作用。缺乏工具，如选择性抑制剂，阻碍了 ERK3 生物学的研究。在这里，我们报告了这种非典型 MAPK 激酶的激酶结构域的晶体结构，为其与经典 MAPK ERK2 的独特 ATP 结合口袋提供了分子见解，解释了它们在抑制剂结合特性上的差异。中等规模的小分子筛选鉴定出了许多抑制剂，其中一些出乎意料地表现出极高的抑制效力。CLK1 与 CAF052 复合物的晶体结构，CAF052 是鉴定出的对 ERK3 最有效的抑制剂之一，揭示了抑制剂的典型 I 型结合模式，通过结构比较，这种模式很可能在 ERK3 中得以维持。结合呈现的结构见解，这些具有可逆和不可逆作用模式的多样化化学支架，将作为开发 ERK3 选择性抑制剂的起点，这将有助于阐明这种研究不足的激酶的重要功能。
