title: Insights into the phosphoryl transfer mechanism of cyclin-dependent protein kinases from ab initio QM/MM free-energy studies.
abstract: 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 Mg(2+) 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.
authors: Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131, USA.
authors: Gregory K
authors: GK
authors: Smith
authors: Zhihong
authors: Z
authors: Ke
authors: Hua
authors: H
authors: Guo
authors: Alvan C
authors: AC
authors: Hengge
mesh_terms: D055162:Biocatalysis; D020134:Catalytic Domain; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D010766:Phosphorylation; D011789:Quantum Theory
chemical_list: D051357:Cyclin-Dependent Kinase 2