Phosphorylation reactions catalyzed by kinases and phosphatases play an indispensible role in cellular signaling, and their malfunctioning is implicated in many diseases. A better understanding of the catalytic mechanism will help design novel and effective mechanism-based inhibitors of these enzymes. In this work, ab initio quantum mechanical/molecular mechanical studies are reported for the phosphoryl transfer reaction catalyzed by a cyclin-dependent kinase, CDK2. Our results suggest that an active-site Asp residue, rather than ATP as previously proposed, serves as the general base to activate the Ser nucleophile. The corresponding transition state features a dissociative, metaphosphate-like structure, stabilized by the Mg2+ ion and several hydrogen bonds. The calculated free-energy barrier is consistent with experimental values. Implications of our results in this and other protein kinases are discussed.
Article
Insights into the Phosphoryl Transfer Mechanism of Cyclin-Dependent Protein Kinases from ab Initio QM/MM Free-EnergyStudies
Journal of Physical Chemistry B
Document Type
Article
Publication Date
1-1-2011
Disciplines
Abstract
Citation Information
Gregory K. Smith, Zhihong Ke, Hua Guo, and Alvan C. Hengge. “Insights into the Phosphoryl
Transfer Mechanism of Cyclin-Dependent Protein Kinases from ab Initio QM/MM Free-Energy
Studies.” J. Phys. Chem. B, 2011, 115 (46), 13713-13722.