Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors.
Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors.
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DOI：
10.1016/j.jbc.2022.102247
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发表时间：
2022-08
影响因子：
4.8
通讯作者：
Bayliss, Richard
中科院分区：
文献类型：
--
作者：
Arter, Chris;Trask, Luke;Ward, Sarah;Yeoh, Sharon;Bayliss, Richard
蛋白激酶是细胞信号传导途径中的关键组分，因为它们主要在Ser、Thr和Tyr残基上进行蛋白质的磷酸化。蛋白激酶的催化活性受到调节，它们可以被认为是通过蛋白质-蛋白质相互作用和翻译后修饰控制的分子开关。蛋白激酶表现出不同的结构调节机制，从30多年前蛋白激酶的第一个晶体结构，到最近通过冷冻电镜的突破对激酶组装的深入了解，一直是结构生物学家的热门课题。蛋白激酶是肿瘤学和其他疾病环境中药物发现的高度优先目标，激酶抑制剂已经改变了特定患者群体的结果。大多数激酶抑制剂是ATP竞争性的，通过占据激酶结构域中心的深疏水口袋来获得效力。抑制剂的选择性取决于利用排列在ATP位点上的氨基酸之间的差异，并探索激酶非活性状态下存在的周围口袋。最近，ATP位点外的变构口袋被靶向以实现高选择性并克服对当前疗法的抗性。在这里，我们回顾了蛋白激酶家族的主要调控特征，描述了不同类型的激酶抑制剂，并强调了激酶调控机制的理解与抑制剂的发展齐头并进的例子。
Protein kinases are key components in cellular signaling pathways as they carry out the phosphorylation of proteins, primarily on Ser, Thr, and Tyr residues. The catalytic activity of protein kinases is regulated, and they can be thought of as molecular switches that are controlled through protein–protein interactions and post-translational modifications. Protein kinases exhibit diverse structural mechanisms of regulation and have been fascinating subjects for structural biologists from the first crystal structure of a protein kinase over 30 years ago, to recent insights into kinase assemblies enabled by the breakthroughs in cryo-EM. Protein kinases are high-priority targets for drug discovery in oncology and other disease settings, and kinase inhibitors have transformed the outcomes of specific groups of patients. Most kinase inhibitors are ATP competitive, deriving potency by occupying the deep hydrophobic pocket at the heart of the kinase domain. Selectivity of inhibitors depends on exploiting differences between the amino acids that line the ATP site and exploring the surrounding pockets that are present in inactive states of the kinase. More recently, allosteric pockets outside the ATP site are being targeted to achieve high selectivity and to overcome resistance to current therapeutics. Here, we review the key regulatory features of the protein kinase family, describe the different types of kinase inhibitors, and highlight examples where the understanding of kinase regulatory mechanisms has gone hand in hand with the development of inhibitors.
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DOI：
10.1073/pnas.92.17.7686
发表时间：
1995-08-15
影响因子：
11.1
作者：
DUDLEY, DT;PANG, L;SALTIEL, AR
通讯作者：
SALTIEL, AR
影响因子：
4
作者：
Kwiatkowski, Nicholas;Deng, Xianming;Wang, Jinhua;Tan, Li;Villa, Fabrizio;Santaguida, Stefano;Huang, Hsiao-Chun;Mitchison, Tim;Musacchio, Andrea;Gray, Nathanael
通讯作者：
Gray, Nathanael
影响因子：
5.8
作者：
Burgess SG;Oleksy A;Cavazza T;Richards MW;Vernos I;Matthews D;Bayliss R
通讯作者：
Bayliss R
影响因子：
4.8
作者：
ALESSI, DR;CUENDA, A;SALTIEL, AR
通讯作者：
SALTIEL, AR
影响因子：
4.8
作者：
Ciuffreda, Ludovica;Del Bufalo, Donatella;Milella, Michele
通讯作者：
Milella, Michele