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  Structure-kinetic relationship study of CDK8/CycC specific compounds

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.

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 Creators:
Schneider, Elisabeth V.1, Author              
Boettcher, Jark2, Author
Huber, Robert1, Author              
Maskos, Klaus2, Author              
Neumann, Lars2, Author
Affiliations:
1Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              
2external, ou_persistent22              

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Free keywords: CYCLIN-DEPENDENT KINASES; RNA-POLYMERASE-II; MAP KINASE; BINDING-KINETICS; PROTEIN-KINASES; RESIDENCE TIME; INHIBITORS; DESIGN; CDK8; COMPLEXESkinetic profiling; structure-based drug design;
 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.

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Language(s): eng - English
 Dates: 2013
 Publication Status: Published in print
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000319803500031
DOI: 10.1073/pnas.1305378110
 Degree: -

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Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Source Genre: Journal
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Publ. Info: 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA : NATL ACAD SCIENCES
Pages: - Volume / Issue: 110 (20) Sequence Number: - Start / End Page: 8081 - 8086 Identifier: ISSN: 0027-8424