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Structure-kinetic relationship study of CDK8/CycC specific compounds

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons78652

Schneider,  Elisabeth V.
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78142

Huber,  Robert
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Schneider, E. V., Boettcher, J., Huber, R., Maskos, K., & Neumann, L. (2013). Structure-kinetic relationship study of CDK8/CycC specific compounds. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(20), 8081-8086. doi:10.1073/pnas.1305378110.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-114A-D
Abstract
In contrast with the very well explored concept of structure-activity relationship, similar studies are missing for the dependency between binding kinetics and compound structure of a protein ligand complex, the structure-kinetic relationship. Here, we present a structure-kinetic relationship study of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex. The scaffold moiety of the compounds is anchored in the kinase deep pocket and extended with diverse functional groups toward the hinge region and the front pocket. These variations can cause the compounds to change from fast to slow binding kinetics, resulting in an improved residence time. The flip of the DFG motif ("DMG" in CDK8) to the inactive DFG-out conformation appears to have relatively little influence on the velocity of binding. Hydrogen bonding with the kinase hinge region contributes to the residence time but has less impact than hydrophobic complementarities within the kinase front pocket.