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Insights into the interaction of high potency inhibitor IRC‐083864 with phosphatase CDC25
Author(s) -
Sarkis Manal,
Miteva Maria A.,
Dasso Lang Maria Chiara,
Jaouen Maryse,
Sari MarieAgnès,
Galcéra MarieOdile,
EthèveQuelquejeu Mélanie,
Garbay Christiane,
Bertho Gildas,
Braud Emmanuelle
Publication year - 2017
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25236
Subject(s) - cdc25 , docking (animal) , chemistry , binding site , active site , stereochemistry , potency , molecular model , phosphatase , enzyme , biochemistry , computational biology , combinatorial chemistry , cell cycle , cell , biology , in vitro , cyclin dependent kinase 1 , medicine , nursing
CDC25 phosphatases play a crucial role in cell cycle regulation. They have been found to be over‐expressed in various human tumours and to be valuable targets for cancer treatment. Here, we report the first model of binding of the most potent CDC25 inhibitor to date, the bis‐quinone IRC‐083864, into CDC25B obtained by combining molecular modeling and NMR studies. Our study provides new insights into key interactions of the catalytic site inhibitor and CDC25B in the absence of any available experimental structure of CDC25 with a bound catalytic site inhibitor. The docking model reveals that IRC‐083864 occupies both the active site and the inhibitor binding pocket of the CDC25B catalytic domain. NMR saturation transfer difference and WaterLOGSY data indicate the binding zones of the inhibitor and support the docking model. Probing interactions of analogues of the two quinone units of IRC‐083864 with CDC25B demonstrate that IRC‐083864 competes with each monomer. Proteins 2017; 85:593–601. © 2016 Wiley Periodicals, Inc.