Lodowski David T, Tesmer Valerie M, Benovic Jeffrey L, Tesmer John J G
Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712-0165, USA.
J Biol Chem. 2006 Jun 16;281(24):16785-93. doi: 10.1074/jbc.M601327200. Epub 2006 Apr 13.
We describe the 2.6-A 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 Galpha(q), although dimerization does not appear to occur in solution and is not required for receptor phosphorylation.
我们描述了人类G蛋白偶联受体激酶（GRK）-6的2.6埃晶体结构，它是多巴胺能信号传导和淋巴细胞趋化性的关键调节因子。GRK6是GRK4亚家族的成员，在大多数（如果不是全部）后生动物中都有。GRK6与GRK2的比较证实，所有GRK的催化核心都由紧密相连的激酶和G蛋白信号调节因子（RGS）同源结构域组成。尽管与ATP类似物结合，但GRK6的激酶结构域仍处于开放状态，推测为无活性构象，这表明G蛋白偶联受体通过诱导激酶结构域关闭来激活GRK。该结构揭示了GRK6 N端附近一个假定的磷脂结合位点以及激酶底物通道内的结构元件，这些元件可能影响G蛋白偶联受体的接近和特异性。晶体GRK6的RGS同源结构域利用与结合Gαq的GRK2中不同的保守疏水残基形成了一个广泛的二聚体界面，尽管二聚化似乎不在溶液中发生，且受体磷酸化也不需要二聚化。
