Molecular basis for activation of G protein-coupled receptor kinases
Open Access
- 20 August 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 29 (19), 3249-3259
- https://doi.org/10.1038/emboj.2010.206
Abstract
G protein‐coupled receptor (GPCR) kinases (GRKs) selectively recognize and are allosterically regulated by activated GPCRs, but the molecular basis for this interaction is not understood. Herein, we report crystal structures of GRK6 in which regions known to be critical for receptor phosphorylation have coalesced to stabilize the kinase domain in a closed state and to form a likely receptor docking site. The crux of this docking site is an extended N‐terminal helix that bridges the large and small lobes of the kinase domain and lies adjacent to a basic surface of the protein proposed to bind anionic phospholipids. Mutation of exposed, hydrophobic residues in the N‐terminal helix selectively inhibits receptor, but not peptide phosphorylation, suggesting that these residues interact directly with GPCRs. Our structural and biochemical results thus provide an explanation for how receptor recognition, phospholipid binding, and kinase activation are intimately coupled in GRKs.Keywords
This publication has 46 references indexed in Scilit:
- Role of the Amino Terminus of G Protein-Coupled Receptor Kinase 2 in Receptor PhosphorylationBiochemistry, 2009
- A Surface of the Kinase Domain Critical for the Allosteric Activation of G Protein-coupled Receptor KinasesPublished by Elsevier BV ,2009
- GRK2 Activation by Receptors: Role of the Kinase Large Lobe and Carboxyl-Terminal TailBiochemistry, 2009
- Structures of Rhodopsin Kinase in Different Ligand States Reveal Key Elements Involved in G Protein-coupled Receptor Kinase ActivationPublished by Elsevier BV ,2008
- Physiological Roles of G Protein–Coupled Receptor Kinases and ArrestinsAnnual Review of Physiology, 2007
- The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory moduleProceedings of the National Academy of Sciences, 2007
- Development of a Yeast Bioassay to Characterize G Protein-coupled Receptor Kinases: IDENTIFICATION OF AN NH2-TERMINAL REGION ESSENTIAL FOR RECEPTOR PHOSPHORYLATIONPublished by Elsevier BV ,2003
- Crystal structure of an activated Akt/Protein Kinase B ternary complex with GSK3-peptide and AMP-PNPNature Structural & Molecular Biology, 2002
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa Crystallographica Section D-Biological Crystallography, 1997
- Identification of the G Protein-coupled Receptor Kinase Phosphorylation Sites in the Human β2-Adrenergic ReceptorPublished by Elsevier BV ,1996