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First BRET‐based screening assay performed in budding yeast leads to the discovery of CDK5/p25 interaction inhibitors
Author(s) -
Corbel Caroline,
Wang Qian,
Bousserouel Hadjira,
Hamdi Amel,
Zhang Bing,
Lozach Olivier,
Ferandin Yoan,
Tan Vincent B. C.,
Guéritte Françoise,
Colas Pierre,
Couturier Cyril,
Bach Stéphane
Publication year - 2011
Publication title -
biotechnology journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.144
H-Index - 84
eISSN - 1860-7314
pISSN - 1860-6768
DOI - 10.1002/biot.201100138
Subject(s) - cyclin dependent kinase 5 , kinase , protein–protein interaction , small molecule , saccharomyces cerevisiae , drug discovery , yeast , biochemistry , förster resonance energy transfer , chemistry , protein kinase a , microbiology and biotechnology , biology , cyclin dependent kinase 2 , physics , quantum mechanics , fluorescence
The protein kinase CDK5 (cyclin‐dependent kinase 5) is activated through its association with a cyclin‐like protein p35 or p39. In pathological conditions (such as Alzheimer's disease and various other neuropathies), truncation of p35 leads to the appearance of the p25 protein. The interaction of p25 with CDK5 up‐regulates the kinase activity and modifies the substrate specificity. ATP‐mimetic inhibitors of CDK5 have already been developed. However, the lack of selectivity of such inhibitors is often a matter of concern. An alternative approach can be used to identify highly specific inhibitors that disrupt protein interactions involving protein kinases. We have developed a bioluminescence resonance energy transfer (BRET)‐based screening assay in yeast to discover protein–protein interaction inhibitors (P2I2). Here, we present the first use of BRET in yeast for the screening of small molecule libraries. This screening campaign led to the discovery of one molecule that prevents the interaction between CDK5 and p25, thus inhibiting the protein kinase activity. This molecule may give rise to high‐specificity drug candidates. Accompanying article Zhang et al.