Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe.

ABSTRACT: G protein-coupled receptor (GPCR) kinases (GRKs) are responsible for initiating desensitization of activated GPCRs. GRK5 is potently inhibited by the calcium-sensing protein calmodulin (CaM), which leads to nuclear translocation of GRK5 and promotion of cardiac hypertrophy. Herein, we report the architecture of the Ca²⁺·CaM-GRK5 complex determined by small-angle X-ray scattering and negative-stain electron microscopy. Ca²⁺·CaM binds primarily to the small lobe of the kinase domain of GRK5 near elements critical for receptor interaction and membrane association, thereby inhibiting receptor phosphorylation while activating the kinase for phosphorylation of soluble substrates. To define the role of each lobe of Ca²⁺·CaM, we utilized the natural product malbran

SUBMITTER: Beyett TS 

PROVIDER: S-EPMC6689901 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature