The structure of G protein-coupled receptor kinase (GRK)-6 defines a second lineage of GRKs
The structure of G protein-coupled receptor kinase (GRK)-6 defines a second lineage of GRKs
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DOI：
10.1074/jbc.m601327200
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发表时间：
2006-06-16
影响因子：
4.8
通讯作者：
Tesmer, John J. G.
中科院分区：
文献类型：
--
作者：
Lodowski, David T.;Tesmer, Valerie M.;Tesmer, John J. G.
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，GRK -6是多巴胺能信号传导和淋巴细胞趋化的关键调节因子。GRK6是grk的GRK4亚家族的成员，在大多数（如果不是全部的话）后生动物中都有。GRK6与GRK2的比较证实，所有GRKs的催化核心都由密切相关的激酶和G蛋白信号（RGS）同源结构域的调节因子组成。尽管与ATP类似物形成复合物，GRK6的激酶结构域仍然保持开放的，可能是无活性的构象，这表明G蛋白偶联受体通过诱导激酶结构域关闭来激活GRKs。该结构揭示了GRK6 N端附近的一个假定的磷脂结合位点，以及激酶底物通道内可能影响G蛋白偶联受体通路和特异性的结构元件。晶体GRK6 RGS同源结构域使用与GRK2中结合G α (q)的保守疏水残基形成广泛的二聚体界面，尽管二聚化似乎不发生在溶液中，也不是受体磷酸化所必需的。
We describe the 2.6-angstrom 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 alpha(q), although dimerization does not appear to occur in solution and is not required for receptor phosphorylation.