Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1798-1809. doi: 10.1080/14756366.2021.1957862.
Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a flavonoid glycoside, binds specifically to RSK1/2 through a binding pocket generated by an extensive conformational rearrangement within the RSK N-terminal kinase domain (NTKD). In modelling experiments a single amino acid that is divergent in RSK3/4 most likely prevents the required conformational rearrangement necessary for SL0101 binding. Kinetic analysis of RSK2 association with SL0101 and its derivatives identified that regions outside of the NTKD contribute to stable inhibitor binding. An analogue with an -propyl-carbamate at the 4" position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors.
鉴定密切相关的激酶家族成员的同工型特异性抑制剂仍然是一个重大的挑战。RSK 家族就是一个很好的例子，它是 ERK1/2 的下游效应物，具有不同的生理作用。天然产物 SL0101 是一种黄酮糖苷，通过 RSK N 端激酶结构域（NTKD）内广泛的构象重排产生的结合口袋特异性地结合 RSK1/2。在建模实验中，RSK3/4 中一个氨基酸的差异很可能阻止了 SL0101 结合所需的构象重排。对 RSK2 与 SL0101 及其衍生物结合的动力学分析表明，NTKD 之外的区域有助于稳定抑制剂的结合。鉴定出一种在鼠李糖部分的 4"位带有丙基氨基甲酸酯的类似物，它与 RSK2 形成高度稳定的抑制剂复合物，但与 RSK1 不形成复合物。这些结果确定了 SL0101 的一种修饰，将有助于鉴定 RSK2 特异性抑制剂。
