Structural and Functional Analysis of G Protein-coupled Receptor Kinase Inhibition by Paroxetine and a Rationally Designed Analog

Homan KT, et al., 85, 237-248, Mol Pharmacol, 2014

With the long-term goal of developing more selective inhibitors of G protein-coupled receptor kinase 2 (GRK2), the authors investigated the molecular basis for the selectivity of paroxetine for GRK2 by directly determining the affinity of paroxetine for various GRKs, its inhibition constants and mechanisms of inhibition for GRK1 and GRK2, and its atomic structure in complex with GRK1, the GRK most weakly inhibited by paroxetine. The Octet RED system and Streptavidin biosensors were used with biotinylated GRKs to characterize the binding of small molecule GRK inhibitors.

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