Cell cycle control by CDKs: chemical biology and structure-guided inhibitor design

The timely controlled catalytic activity of some cyclin-dependent kinases contributes to the progression through the phases of the cell division cycle to the mitosis. The functions and regulations of cell cycle have been extensively studied. Despite that, we have an active interest in the link between their structural, functional properties and identities (ie what specific determinants make a given CDK its properties? This is an important question to (i) design ways to comprehend the specific function of a CDK, given the fact that genetic studies can be limited due to the functional redundancy of CDKs and (ii) design more selective ways to inhibit a CDK. Following are two examples of the work that we have contributed in these areas.


We have been working in collaboration with Dr. D. Fisher’s team (IGMM), leader in this project, on developing some chemical/biochemical tools to elucidate the role of CDK1/CDK2 and their functional redundancy. Using a multidisciplinary approach, our data supports the view that CDK2 has a rate-limiting role in DNA replication. Further exploring this role, we designed, tested and structurally characterised inhibitor-resistant-CDK2 mutants that confirmed that CDK2 activity is rate-limiting in replication.

The strength of this work resides in the use of a broad multidisciplinary approach that spans from bio-informatics, mathematical modelling of enzymology data, structural biology and functional analysis on Xenopus egg extracts. This work has been published in Chemistry & Biology:

Echalier, A.*, Cot, E.*, Camasses, A. *, Hodimont, E., Hoh, F., Jay, P., Sheinerman, F. Krasinska, L. and Fisher, D. An integrated chemical biology approach provides insight into CDK2 functional redundancy and inhibitor sensitivity. (2012). Chem. & Biol. 19(8), 1028-1040. * equal contribution


This work has been supported by (for our contribution): the Université Montpellier I, the CNRS, and the INSERM.

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