Journal article

Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex with a Rationally Designed Inhibitor

Kristoff T Homan, Helen V Waldschmidt, Alisa Glukhova, Alessandro Cannavo, Jianliang Song, Joseph Y Cheung, Walter J Koch, Scott D Larsen, John JG Tesmer

Journal of Biological Chemistry | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2015

Abstract

G protein-coupled receptor kinases (GRKs) regulate cell signaling by initiating the desensitization of active G protein-coupled receptors. The two most widely expressed GRKs (GRK2 and GRK5) play a role in cardiovascular disease and thus represent important targets for the development of novel therapeutic drugs. In the course of a GRK2 structure-based drug design campaign, one inhibitor (CCG215022) exhibited nanomolar IC50 values against both GRK2 and GRK5 and good selectivity against other closely related kinases such as GRK1 and PKA. Treatment of murine cardiomyocytes with CCG215022 resulted in significantly increased contractility at 20-fold lower concentrations than paroxetine, an inhibit..

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Grants

Awarded by United States Department of Energy, Office of Science, Office of Basic Energy Sciences


Awarded by Michigan Technology Tri-Corridor Grant


Awarded by National Institutes of Health


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Funding Acknowledgements

We thank Dr. Jeffrey L. Benovic and Dr. Konstanin Komolov for reading and providing feedback on the manuscript and for providing their atomic coordinates in advance of publication. We also thank Kelly L. Larimore for technical assistance. Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract DE-AC02-06CH11357, and use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corp. and Michigan Technology Tri-Corridor Grant 085P1000817. is research used the DNA Sequencing Core of the Michigan Diabetes Research and Training Center supported by National Institutes of Health Grant DK20572.