Identification of residues involved in neurotensin binding and modeling of the agonist binding site in neurotensin receptor 1
Identification of residues involved in neurotensin binding and modeling of the agonist binding site in neurotensin receptor 1
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DOI：
10.1074/jbc.275.1.328
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发表时间：
2000-01-07
影响因子：
4.8
通讯作者：
Labbé-Jullié, C
中科院分区：
文献类型：
--
作者：
Barroso, S;Richard, F;Labbé-Jullié, C
神经降压素受体1（NTR 1）亚型属于G蛋白偶联受体家族，并介导神经肽的大多数已知作用，包括调节中枢多巴胺能传递。这表明作用于NTR 1的非肽激动剂模拟物可能有助于治疗帕金森病和精神分裂症。在此，我们试图确定神经降压素的药效团神经降压素-（8-13）与大鼠NTR 1之间的分子相互作用，NTR 1的突变鉴定了与神经降压素相互作用的残基，神经降压素-（8-13）类似物的结构-活性研究鉴定了与受体中突变氨基酸相互作用的肽残基。通过考虑这些数据，使用计算机辅助建模技术来构建神经降压素-（8-13）-结合位点的三维模型，其中神经降压素（8- 13）的N-末端四肽适合于第三胞外环，并且C-末端二肽结合于受体的胞外结构域和跨膜结构域之间的连接处的残基。有趣的是，激动剂结合位点位于前面描述的NTR 1结合位点的非肽类神经降压素拮抗剂SR 48692，我们的数据提供了一个基础，在分子水平上的激动剂和拮抗剂的结合模式的理解，并可能有助于设计非肽类激动剂模拟NTR 1。
The neurotensin receptor 1 (NTR1) subtype belongs to the family of G protein-coupled receptors and mediates most of the known effects of the neuropeptide including modulation of central dopaminergic transmission. This suggested that nonpeptide agonist mimetics acting at the NTR1 might be helpful in the treatment of Parkinson's disease and schizophrenia. Here, we attempted to define the molecular interactions between neurotensin-(8-13), the pharmacophore of neurotensin, and the rat NTR1, Mutagenesis of the NTR1 identified residues that interact with neurotensin, Structure-activity studies with neurotensin-(8-13) analogs identified the peptide residues that interact with the mutated amino acids in the receptor. By taking these data into account, computer-assisted modeling techniques were used to build a tridimensional model of the neurotensin-(8-13)-binding site in which the N-terminal tetrapeptide of neurotensin(8-13) fits in the third extracellular loop and the C-terminal dipeptide binds to residues at the junction between the extracellular and transmembrane domains of the receptor. Interestingly, the agonist binding site lies on top of the previously described NTR1-binding site for the nonpeptide neurotensin antagonist SR 48692, Our data provide a basis for understanding at the molecular level the agonist and antagonist binding modes and may help design nonpeptide agonist mimetics of the NTR1.