Home
Resources
Publications
Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex With a Rationally Designed Inhibitor

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 J G Tesmer

J Biol Chem. 2015 Aug 21;290(34):20649-59.

PMID: 26032411

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP817194380	GSK180736A		817194-38-0	Price
CS31042719	Paroxetine Related Compound G			Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: