Open AccessInhibition of Cyclin‐Dependent Kinases by Purine Analogues
Author(s) -
Azevedo Walter Filgueira,
Leclerc Sophie,
Meijer Laurent,
Havlicek Libor,
Strnad Miroslav,
Kim SungHou
Publication year - 1997
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1997.0518a.x
Subject(s) - cyclin dependent kinase , cyclin dependent kinase 1 , cyclin dependent kinase 2 , stereochemistry , kinase , cdk inhibitor , cyclin dependent kinase complex , cyclin a , chemistry , purine analogue , cell cycle , enzyme , biochemistry , purine , protein kinase a , cell
Cyclin‐dependent kinases (cdk) control the cell division cycle (cdc). These kinases and their regulators are frequently deregulated in human tumours. A potent inhibitor of cdks, roscovitine [2‐(1‐ethyl‐2‐hydroxyethylamino)‐6‐benzylamino‐9‐isopropylpurine], was identified by screening a series of C2,N 6 , N 9 ‐sub‐stituted adenines on purified cdc2/cyclin B. Roscovitine displays high efficiency and high selectivity (Meijer, L., Borgne, A., Mulner, O., Chong, J. P. J., Blow, J. J., Inagaki, N., Inagaki, M., Delcros, J.‐G. & Moulinoux, J.‐P. (1997) Eur. J. Biochem. 243 , 527–536). It behaves as a competitive inhibitor for ATP binding to cdc2. We determined the crystal structure of a complex between cdk2 and roscovitine at 0.24‐nm (2.4 Å) resolution and refined to an R factor of 0.18. The purine portion of the inhibitor binds to the adenine binding pocket of cdk2. The position of the benzyl ring group of the inhibitor enables the inhibitor to make contacts with the enzyme not observed in the ATP‐complex structure. Analysis of the position of this benzyl ring explains the specificity of roscovitine in inhibiting cdk2. The structure also reveals that the ( R )‐stereoisomer of roscovitine is bound to cdk2. The ( R )isomer is about twice as potent in inhibiting cdc2/cyclin B than the ( S )‐isomer. Results from structure/activity studies and from analysis of the cdk2/roscovitine complex crystal structure should allow the design of even more potent cdk inhibitors.