Controlling Kinase Activities by Selective Inhibition of Peptide Substrates
Controlling Kinase Activities by Selective Inhibition of Peptide Substrates
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DOI：
10.1021/jacs.0c11566
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发表时间：
2021-01-04
影响因子：
15
通讯作者：
Zhao, Yan
中科院分区：
文献类型：
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作者：
Li, Xiaowei;Zanela, Tania M. Palhano;Zhao, Yan
磷酸化是蛋白质最常见的可逆翻译后修饰（PTM）。由于给定的激酶通常在细胞中具有许多底物，并且参与许多功能，因此对酶的传统抑制会导致意想不到的后果。在这里，我们报告合成受体，以操纵激酶磷酸化精确的第一次，利用受体的能力，结合肽具有高亲和力和特异性。该抑制能够使混合物中具有相同共有基序的肽选择性磷酸化。一个特定的磷酸化位点可以被抑制，而同一底物中的其他位点进行磷酸化。受体可以单独作用于其靶链，也可以协同保护长序列的片段。结合衍生的抑制能够与多结构域激酶内的蛋白质-蛋白质相互作用竞争，使得能够以先前不可用的方式进行受控的PTM。
Phosphorylation is the most common reversible post-translational modification (PTM) of proteins. Because a given kinase often has many substrates in a cell and is involved in numerous functions, traditional inhibition of the enzyme leads to unintended consequences. Here we report synthetic receptors to manipulate kinase phosphorylation precisely for the first time, utilizing the receptors' abilities to bind peptides with high affinity and specificity. The inhibition enables selective phosphorylation of peptides with identical consensus motifs in a mixture. A particular phosphosite can be inhibited while other sites in the same substrate undergo phosphorylation. The receptors may work either individually on their targeted strands or in concert to protect segments of a long sequence. The binding-derived inhibition is able to compete with protein-protein interactions within a multidomain kinase, enabling controlled PTM to be performed in a previously unavailable manner.