Briefly Bound to Activate: Transient Binding of a Second Catalytic Magnesium Activates the Structure and Dynamics of CDK2 Kinase for Catalysis
- Michigan-Med
We have determined high-resolution crystal structures of a CDK2/Cyclin A transition state complex bound to ADP, substrate peptide, and MgF{sub 3}{sup -}. Compared to previous structures of active CDK2, the catalytic subunit of the kinase adopts a more closed conformation around the active site and now allows observation of a second Mg{sup 2+} ion in the active site. Coupled with a strong [Mg{sup 2+}] effect on in vitro kinase activity, the structures suggest that the transient binding of the second Mg{sup 2+} ion is necessary to achieve maximum rate enhancement of the chemical reaction, and Mg{sup 2+} concentration could represent an important regulator of CDK2 activity in vivo. Molecular dynamics simulations illustrate how the simultaneous binding of substrate peptide, ATP, and two Mg{sup 2+} ions is able to induce a more rigid and closed organization of the active site that functions to orient the phosphates, stabilize the buildup of negative charge, and shield the subsequently activated {gamma}-phosphate from solvent.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- OTHER
- OSTI ID:
- 1031377
- Journal Information:
- Structure, Vol. 19, Issue (5) ; 05, 2011
- Country of Publication:
- United States
- Language:
- ENGLISH
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