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

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Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein-coupled Receptor Kinases.

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

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Song, Jianliang Glukhova, Alisa Tesmer, John J. G. Cheung, Joseph Y. Koch, Walter J. Waldschmidt, Helen V. Larsen, Scott D. Homan, Kristoff T. Cannavo, Alessandro
Description	Author Affiliation: Homan KT ( From the Life Sciences Institute and the Departments of Pharmacology and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109.); Waldschmidt HV ( the Vahlteich Medicinal Chemistry Core and the Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, and.); Glukhova A ( From the Life Sciences Institute and the Departments of Pharmacology and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109.); Cannavo A ( the Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.); Song J ( the Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.); Cheung JY ( the Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.); Koch WJ ( the Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.); Larsen SD ( the Vahlteich Medicinal Chemistry Core and the Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, and.); Tesmer JJ ( From the Life Sciences Institute and the Departments of Pharmacology and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, tesmerjj@umich.edu.)
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 inhibitor with more modest selectivity for GRK2. A 2.4 Å crystal structure of the GRK5·CCG215022 complex was determined and revealed that the inhibitor binds in the active site similarly to its parent compound GSK180736A. As designed, its 2-pyridylmethyl amide side chain occupies the hydrophobic subsite of the active site where it forms three additional hydrogen bonds, including one with the catalytic lysine. The overall conformation of the GRK5 kinase domain is similar to that of a previously determined structure of GRK6 in what is proposed to be its active state, but the C-terminal region of the enzyme adopts a distinct conformation. The kinetic properties of site-directed mutants in this region are consistent with the hypothesis that this novel C-terminal structure is representative of the membrane-bound conformation of the enzyme.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	34
Volume Number	290
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2015-08-21
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cardiovascular Agents Chemistry Enzyme Inhibitors G-Protein-Coupled Receptor Kinase 5 Myocytes, Cardiac Drug Effects Pyridines Animals Chemical Synthesis Pharmacology Catalytic Domain Crystallography, X-Ray Drug Design Genetics Isolation & Purification Gene Expression Heart Septum Cytology Enzymology Heart Ventricles Hydrogen Bonding Hydrophobic And Hydrophilic Interactions Kinetics Mice Models, Molecular Molecular Sequence Data Mutation Myocardial Contraction Paroxetine Protein Interaction Domains And Motifs Protein Structure, Secondary Sequence Alignment Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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