Insights into the interaction of high potency inhibitor IRC‐083864 with phosphatase CDC25. Issue 4 (18th January 2017)

• Record Type: Journal Article
• Authors: Sarkis, Manal; Miteva, Maria A.; Dasso Lang, Maria Chiara; Jaouen, Maryse; Sari, Marie‐Agnès; Galcéra, Marie‐Odile; Ethève‐Quelquejeu, Mélanie; Garbay, Christiane; Bertho, Gildas; Braud, Emmanuelle
• Is Part Of: Proteins. Volume 85:Issue 4(2017)
• Page Start: 593
• Page End: 601
• Publication Date: 2017-01-18
• Subjects: STD‐NMR -- WaterLOGSY -- docking -- cancer -- protein–ligand binding; Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.25236
• Languages: English
• ISSNs: 0887-3585

Abstract

ABSTRACT: 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.