Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 115, Issue 46, Pages 13713-13722Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jp207532s
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Funding
- National Institutes of Health [R01-047297]
- NSMS IGERT
- National Science Foundation
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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.
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