Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles

ChemPhysChem ◽  
2017 ◽  
Vol 18 (7) ◽  
pp. 785-795 ◽  
Author(s):  
Michaela Nekardová ◽  
Ladislava Vymětalová ◽  
Prashant Khirsariya ◽  
Silvia Kováčová ◽  
Michaela Hylsová ◽  
...  
Keyword(s):  
Structural Basis ◽  
Cyclin Dependent Kinase

scholarly journals Structural basis of divergent cyclin‐dependent kinase activation by Spy1/ RINGO proteins

2017 ◽  
Vol 36 (15) ◽  
pp. 2251-2262 ◽  
Author(s):  
Denise A McGrath ◽  
Bre‐Anne Fifield ◽  
Aimee H Marceau ◽  
Sarvind Tripathi ◽  
Lisa A Porter ◽  
...  
Keyword(s):  
Structural Basis ◽  
Cyclin Dependent Kinase ◽  
Kinase Activation

Structural basis of cyclin-dependent kinase activation by phosphorylation

1996 ◽  
Vol 3 (8) ◽  
pp. 696-700 ◽  
Author(s):  
Alicia A. Russo ◽  
Philip D. Jeffrey ◽  
Nikola P. Pavletich
Keyword(s):  
Structural Basis ◽  
Cyclin Dependent Kinase ◽  
Kinase Activation

scholarly journals Comparative Modeling of CDK9 Inhibitors to Explore Selectivity and Structure-Activity Relationships

2020 ◽  
Author(s):  
Palani Kirubakaran ◽  
George Morton ◽  
Pingfeng Zhang ◽  
Hanghang Zhang ◽  
John Gordon ◽  
...  
Keyword(s):  
Structural Changes ◽  
Comparative Modeling ◽  
Data Bank ◽  
Structural Basis ◽  
Type I ◽  
Cyclin Dependent Kinase ◽  
Active Conformation ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Promising Target

AbstractCyclin-dependent kinase 9 (CDK9) plays a key role in transcription elongation, and more recently it was also identified as the molecular target of a series of diaminothiazole compounds that reverse epigenetic silencing in a phenotypic assay. To better understand the structural basis underlying these compounds’ activity and selectivity, we developed a comparative modeling approach that we describe herein. Briefly, this approach draws upon the strong structural conservation across the active conformation of all protein kinases, and their shared pattern of interactions with Type I inhibitors. Because of this, we hypothesized that the large collection of inhibitor/kinase structures available in the Protein Data Bank (PDB) would enable accurate modeling of this diaminothiazole series in complex with each CDK family member. We apply this new comparative modeling pipeline to build each of these structural models, and then demonstrate that these models provide retrospective rationale for the structure-activity relationships that ultimately guided optimization to the lead diaminothiazole compound MC180295 (14e). We then solved the crystal structure of the 14e/CDK9 complex, and found the resulting structure to be in excellent agreement with our corresponding comparative model. Finally, inspired by these models, we demonstrate how structural changes to 14e can be used to rationally tune this compound’s selectivity profile. With the emergence of CDK9 as a promising target for therapeutic intervention in cancer, we anticipate that comparative modeling can provide a valuable tool to guide optimization of potency and selectivity of new inhibitors targeting this kinase.

Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol

2002 ◽  
Vol 293 (1) ◽  
pp. 566-571 ◽  
Author(s):  
Walter Filgueira de Azevedo ◽  
Fernanda Canduri ◽  
Nelson José Freitas da Silveira
Keyword(s):  
Structural Basis ◽  
Cyclin Dependent Kinase

Site-Specific Phosphorylation of Lys-Ser-Pro Repeat Peptides from Neurofilament H by Cyclin-Dependent Kinase 5:  Structural Basis for Substrate Recognition

Biochemistry ◽  
1998 ◽  
Vol 37 (14) ◽  
pp. 4759-4766 ◽  
Author(s):  
Pushkar Sharma ◽  
Joseph J. Barchi, ◽  
Xiaolin Huang ◽  
Niranjana D. Amin ◽  
Howard Jaffe ◽  
...  
Keyword(s):  
Substrate Recognition ◽  
Structural Basis ◽  
Cyclin Dependent Kinase ◽  
Site Specific ◽  
Cyclin Dependent Kinase 5

Cyclin-Dependent Kinase 2 in Cellular Senescence and Cancer. A Structural and Functional Review

2019 ◽  
Vol 20 (7) ◽  
pp. 716-726 ◽  
Author(s):  
Priscylla Andrade Volkart ◽  
Gabriela Bitencourt-Ferreira ◽  
André Arigony Souto ◽  
Walter Filgueira de Azevedo
Keyword(s):  
Binding Affinity ◽  
Cellular Senescence ◽  
Cell Cycle Progression ◽  
Structural Information ◽  
Structural Basis ◽  
Cyclin Dependent Kinase ◽  
New Era ◽  
Functional Studies ◽  
Molecular Aspects

<P>Background: Cyclin-dependent kinase 2 (CDK2) has been studied due to its role in the cell-cycle progression. The elucidation of the CDK2 structure paved the way to investigate the molecular basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with functional studies. </P><P> Objective: Our goal here is to review recent functional and structural studies directed to understanding the role of CDK2 in cancer and senescence. </P><P> Methods: There are over four hundreds of crystallographic structures available for CDK2, many of them with binding affinity information. We use this abundance of data to analyze the essential features responsible for the inhibition of CDK2 and its function in cancer and senescence. </P><P> Results: The structural and affinity data available CDK2 makes it possible to have a clear view of the vital CDK2 residues involved in molecular recognition. A detailed description of the structural basis for ligand binding is of pivotal importance in the design of CDK2 inhibitors. Our analysis shows the relevance of the residues Leu 83 and Asp 86 for binding affinity. The recent findings revealing the participation of CDK2 inhibition in senescence open the possibility to explore the richness of structural and affinity data for a new era in the development of CDK2 inhibitors, targeting cellular senescence. </P><P> Conclusion: Here, we analyzed structural information for CDK2 in combination with inhibitors and mapped the molecular aspects behind the strongest CDK2 inhibitors for which structures and ligandbinding affinity data were available. From this analysis, we identified the significant intermolecular interactions responsible for binding affinity. This knowledge may guide the future development of CDK2 inhibitors targeting cancer and cellular senescence.</P>

Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a

Nature ◽  
10.1038/26155 ◽  
1998 ◽  
Vol 395 (6699) ◽  
pp. 237-243 ◽  
Author(s):  
Alicia A. Russo ◽  
Lily Tong ◽  
Jie-Oh Lee ◽  
Philip D. Jeffrey ◽  
Nikola P. Pavletich
Keyword(s):  
Tumour Suppressor ◽  
Structural Basis ◽  
Cyclin Dependent Kinase
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