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J. Biol. Chem., Vol. 281, Issue 24, 16785-16793, June 16, 2006

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The Structure of G Protein-coupled Receptor Kinase (GRK)-6 Defines a Second Lineage of GRKs^*

David T. Lodowski, Valerie M. Tesmer, Jeffrey L. Benovic^¶, and John J. G. Tesmer¹

From the Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712-0165, the Life Sciences Institute, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-2216, and the ^¶Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

We describe the 2.6-Å crystal structure of human G protein-coupled receptor kinase (GRK)-6, a key regulator of dopaminergic signaling and lymphocyte chemotaxis. GRK6 is a member of the GRK4 subfamily of GRKs, which is represented in most, if not all, metazoans. Comparison of GRK6 with GRK2 confirms that the catalytic core of all GRKs consists of intimately associated kinase and regulator of G protein signaling (RGS) homology domains. Despite being in complex with an ATP analog, the kinase domain of GRK6 remains in an open, presumably inactive conformation, suggesting that G protein-coupled receptors activate GRKs by inducing kinase domain closure. The structure reveals a putative phospholipid-binding site near the N terminus of GRK6 and structural elements within the kinase substrate channel that likely influence G protein-coupled receptor access and specificity. The crystalline GRK6 RGS homology domain forms an extensive dimer interface using conserved hydrophobic residues distinct from those in GRK2 that bind G_q, although dimerization does not appear to occur in solution and is not required for receptor phosphorylation.

Received for publication, February 10, 2006 , and in revised form, March 29, 2006.

^* This work was supported by American Heart Association Scientist Development Grant 0235273N, National Institutes of Health Grant HL071818, American Cancer Society Research Scholar Grant 04-185-01, and a Research Corporation Cottrell Scholar grant (to J. J. G. T.) and by National Institutes of Health Grant GM44944 (to J. L. B.). The work performed at the Advanced Light Source was supported by Contract DE-AC03-76SF00098 from the Office of Science, Office of Basic Energy Sciences, Materials Sciences Division, United States Department of Energy (to the Lawrence Berkeley National Laboratory). Proteomics data were provided by the Michigan Proteome Consortium (available at www.proteomeconsortium.org), which is supported in part by the Michigan Life Sciences Corridor. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and supplemental Refs. 1 and 2.

The atomic coordinates and structure factors (code 2ACX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ To whom correspondence should be addressed: Life Sciences Inst., Dept. of Pharmacology, University of Michigan, 210 Washtenaw Ave., Ann Arbor, MI 48109-2216. Tel.: 734-615-9544; Fax: 734-763-6492; E-mail: johntesmer{at}umich.edu.

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