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Science 23 May 2003:
Vol. 300. no. 5623, pp. 1256 - 1262
DOI: 10.1126/science.1082348
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Research Articles

Keeping G Proteins at Bay: A Complex Between G Protein-Coupled Receptor Kinase 2 and Gß{gamma}

David T. Lodowski,1 Julie A. Pitcher,2 W. Darrell Capel,3 Robert J. Lefkowitz,3 John J. G. Tesmer1*

The phosphorylation of heptahelical receptors by heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor kinases (GRKs) is a universal regulatory mechanism that leads to desensitization of G protein signaling and to the activation of alternative signaling pathways.We determined the crystallographic structure of bovine GRK2 in complex with G protein ß1{gamma}2 subunits.Our results show how the three domains of GRK2–the RGS (regulator of G protein signaling) homology, protein kinase, and pleckstrin homology domains–integrate their respective activities and recruit the enzyme to the cell membrane in an orientation that not only facilitates receptor phosphorylation, but also allows for the simultaneous inhibition of signaling by G{alpha} and Gß{gamma} subunits.

1 Institute for Cellular and Molecular Biology, Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA.
2 MRC Laboratory for Molecular and Cell Biology and Cell Biology Unit, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
3 Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

* To whom correspondence should be addressed. E-mail: tesmer{at}mail.utexas.edu

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