Identifying requirements for RSK2 specific inhibitors.
Identifying requirements for RSK2 specific inhibitors.
复制标题
确定对RSK2特异性抑制剂的要求。
DOI：
10.1080/14756366.2021.1957862
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发表时间：
2021-12
影响因子：
5.6
通讯作者：
Lannigan DA
中科院分区：
文献类型：
--
作者：
Wright EB;Fukuda S;Li M;Li Y;O'Doherty GA;Lannigan DA
鉴定密切相关的激酶家族成员的异构体特异性抑制剂仍然是一个巨大的挑战。RSK家族是ERK 1/2的下游效应子，具有不同的生理效应，这说明了实现这种特异性的必要性。天然产物SL 0101是一种类黄酮糖苷，通过RSK N-末端激酶结构域（NTKD）内广泛构象重排产生的结合口袋特异性结合RSK 1/2。在建模实验中，RSK 3/4中趋异的单个氨基酸最有可能阻止SL 0101结合所需的构象重排。RSK 2与SL 0101及其衍生物结合的动力学分析表明，NTKD以外的区域有助于稳定的抑制剂结合。鉴定了在鼠李糖部分的4”位具有正丙基氨基甲酸酯的类似物，其与RSK 2形成高度稳定的抑制剂复合物，但不与RSK 1形成高度稳定的抑制剂复合物。这些结果鉴定了有助于鉴定RSK 2特异性抑制剂的SL 0101修饰。
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 n-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.
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影响因子：
5.7
作者：
Ludwik KA;Campbell JP;Li M;Li Y;Sandusky ZM;Pasic L;Sowder ME;Brenin DR;Pietenpol JA;O'Doherty GA;Lannigan DA
通讯作者：
Lannigan DA
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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