1YM7

G Protein-Coupled Receptor Kinase 2 (GRK2)

Summary for 1YM7

• Entry DOI: 10.2210/pdb1ym7/pdb
• Related: 1OMW
• Descriptor: Beta-adrenergic receptor kinase 1 (1 entity in total)
• Functional Keywords: g protein, kinase, gpcr, grk2, beta-ark1, transferase
• Biological source: Bos taurus (cattle)
• Total number of polymer chains: 4
• Total formula weight: 318999.69

Authors

Lodowski, D.T.,Barnhill, J.F.,Pyskadlo, R.M.,Ghirlando, R.,Sterne-Marr, R.,Tesmer, J.J.G. (deposition date: 2005-01-20, release date: 2005-07-05, Last modification date: 2023-08-23)

Primary citation

Lodowski, D.T.,Barnhill, J.F.,Pyskadlo, R.M.,Ghirlando, R.,Sterne-Marr, R.,Tesmer, J.J.G.
The role of Gbetagamma and domain interfaces in the activation of G protein-coupled receptor kinase 2
Biochemistry, 44:6958-6970, 2005

PubMed Abstract: In response to extracellular signals, G protein-coupled receptors (GPCRs) catalyze guanine nucleotide exchange on Galpha subunits, enabling both activated Galpha and Gbetagamma subunits to target downstream effector enzymes. One target of Gbetagamma is G protein-coupled receptor kinase 2 (GRK2), an enzyme that initiates homologous desensitization by phosphorylating activated GPCRs. GRK2 consists of three distinct domains: an RGS homology (RH) domain, a protein kinase domain, and a pleckstrin homology (PH) domain, through which it binds Gbetagamma. The crystal structure of the GRK2-Gbetagamma complex revealed that the domains of GRK2 are intimately associated and left open the possibility for allosteric regulation by Gbetagamma. In this paper, we report the 4.5 A structure of GRK2, which shows that the binding of Gbetagamma does not induce large domain rearrangements in GRK2, although small rotations of the RH and PH domains relative to the kinase domain are evident. Mutation of residues within the larger domain interfaces of GRK2 generally leads to diminished expression and activity, suggesting that these interfaces are important for stability and remain intact upon activation of GRK2. Geranylgeranylated Gbetagamma, but not a soluble mutant of Gbetagamma, protects GRK2 from clostripain digestion at a site within its kinase domain that is 80 A away from the Gbetagamma binding site. Equilibrium ultracentrifugation experiments indicate that neither abnormally large detergent micelles nor protein oligomerization can account for the observed protection. The Gbetagamma-mediated binding of GRK2 to CHAPS micelles or lipid bilayers therefore appears to rigidify the kinase domain, perhaps by encouraging stable contacts between the RH and kinase domains.

PubMed: 15865441
DOI: 10.1021/bi050119q

Experimental method

X-RAY DIFFRACTION (4.5 Å)