Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2.
Cyclin-dependent kinase 2 (CDK2) is a crucial regulator of the eukaryotic cell cycle. However it is well established that monomeric CDK2 lacks regulatory activity, which needs to be aroused by its positive regulators, cyclins E and A, or be phosphorylated on the catalytic segment. Interestingly, these activation steps bring some dynamic changes on the 3D-structure of the kinase, especially the activation segment. Until now, in the monomeric CDK2 structure, three binding sites have been reported, including the adenosine triphosphate (ATP) binding site (Site I) and two non-competitive binding sites (Site II and III). In addition, when the kinase is subjected to the cyclin binding process, the resulting structural changes give rise to a variation of the ATP binding site, thus generating an allosteric binding site (Site IV). All the four sites are demonstrated as being targeted by corresponding inhibitors, as is illustrated by the allosteric binding one which is targeted by inhibitor ANS (ﬂuorophore 8-anilino-1-naphthalene sulfonate). In the present work, the binding mechanisms and their fluctuations during the activation process attract our attention. Therefore, we carry out corresponding studies on the structural characterization of CDK2, which are expected to facilitate the understanding of the molecular mechanisms of kinase proteins. Besides, the binding mechanisms of CDK2 with its relevant inhibitors, as well as the changes of binding mechanisms following conformational variations of CDK2, are summarized and compared. The summary of the conformational characteristics and ligand binding mechanisms of CDK2 in the present work will improve our understanding of the molecular mechanisms regulating the bioactivities of CDK2.
Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. yanli@dlut.edu.cn.
Yan
Y
Li
Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. zhanglilei@outlook.com.|School of Chemistry and Environmental Engineering, Hubei University for Nationalities, Enshi 445000, China. zhanglilei@outlook.com.
Jingxiao
J
Zhang
Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. weimingao@mail.dlut.edu.cn.
Weimin
W
Gao
School of Chemistry and Environmental Engineering, Hubei University for Nationalities, Enshi 445000, China. zhanglilei@outlook.com.
Lilei
L
Zhang
Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. yqpan@dlut.edu.cn.
Yanqiu
Y
Pan
Key laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. zswei@dlut.edu.cn.
Shuwei
S
Zhang
Center of Bioinformatics, College of Life Science, Northwest A&F University, Yangling 712100, China. yh_wang@nwsuaf.edu.cn.
Yonghua
Y
Wang
D000255:Adenosine Triphosphate / Q000737:chemistry; D000495:Allosteric Site; D000595:Amino Acid Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002384:Catalysis; D002986:Clinical Trials as Topic; D019925:Cyclin A / Q000737:chemistry; D019926:Cyclin B / Q000737:chemistry; D019927:Cyclin E / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D019925:Cyclin A; D019926:Cyclin B; D019927:Cyclin E; D008024:Ligands; D000255:Adenosine Triphosphate; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2