NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor
NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor
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DOI：
10.1073/pnas.0404702101
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发表时间：
2004-08-31
影响因子：
11.1
通讯作者：
Riek, R
中科院分区：
文献类型：
--
作者：
Grace, CRR;Perrin, MH;Riek, R
促肾上腺皮质激素释放因子 (CRF) 配体家族对中枢神经系统具有多种影响，包括调节应激反应。配体的作用是通过与 CRF G 蛋白偶联受体结合来介导的。我们确定了小鼠CRF受体2β的N端胞外结构域（ECD1）的3D NMR结构，该结构域是主要的配体识别结构域，并通过化学位移微扰实验鉴定了其配体结合位点。该折叠被确定为短共有重复序列 (SCR)，这是一种常见的蛋白质相互作用模块。诱变揭示了全长受体中激素结合位点的完整性。这项研究提出，ECD1 捕获配体的 C 端片段，然后其 N 端渗透到受体的跨膜区域以启动信号传导。 ECD1 中 SCR 的关键残基在 G 蛋白偶联受体亚家族中是保守的，表明该亚家族的所有 ECD(1) 中都有 SCR 折叠。
The corticotropin-releasing factor (CRF) ligand family has diverse effects on the CNS, including the modulation of the stress response. The ligands' effects are mediated by binding to CRF G protein-coupled receptors. We have determined the 3D NMR structure of the N-terminal extracellular domain (ECD1) of the mouse CRF receptor 2beta, which is the major ligand recognition domain, and identified its ligand binding site by chemical-shift perturbation experiments. The fold is identified as a short consensus repeat (SCR), a common protein interaction module. Mutagenesis reveals the integrity of the hormone-binding site in the full-length receptor. This study proposes that the ECD1 captures the C-terminal segment of the ligand, whose N terminus then penetrates into the transmembrane region of the receptor to initiate signaling. Key residues of SCR in the ECD1 are conserved in the G protein-coupled receptor subfamily, suggesting the SCR fold in all of the ECD(1)s of this subfamily.